Substituted n,2-diarylquinoline-4-carboxamides and the use thereof as anti-inflammatory agents

ABSTRACT

The present application relates to novel substituted N,2-diarylquinoline-4-carboxamide derivatives, to processes for preparation thereof, to the use thereof alone or in combinations for treatment and/or prevention of diseases, and to the use thereof for production of medicaments for treatment and/or prevention of diseases, especially for treatment and/or prevention of fibrotic and/or inflammatory disorders.

The present application relates to novel substitutedN,2-diarylquinoline-4-carboxamide derivatives, to processes forpreparation thereof, to the use thereof alone or in combinations fortreatment and/or prevention of diseases, and to the use thereof forproduction of medicaments for treatment and/or prevention of diseases,especially for treatment and/or prevention of fibrotic and/orinflammatory disorders.

Prostaglandin F2alpha (PGF2α) is part of the family of bioactiveprostaglandins, which are derivatives of arachidonic acid. After releasefrom membrane phospholipids by A2 phospholipases, arachidonic acid isoxidized by cyclooxygenases to prostaglandin H2 (PGH2), which isconverted further by PGF synthase to PGF2α. PGF2α can also be formedenzymatically in a much smaller proportion from other prostaglandinssuch as PGE2 or PGD2 [Watanabe et al., J. Biol. Chem. 1985,260:7035-7041]. PGF2α is not stored, but is released immediately aftersynthesis, as a result of which it displays its effects locally. PGF2αis an unstable molecule (t_(1/2)<1 minute), which is rearranged rapidlyby enzymatic means in the lung, liver and kidney to give an inactivemetabolite, 15-ketodihydro-PGF2α [Basu et al., Acta Chem. Scand. 1992,46:108-110]. 15-Ketodihydro-PGF2α is detectable in relatively largeamounts in the plasma and later also in the urine, both underphysiological and pathophysiological conditions.

The biological effects of PGF2α come about through the binding andactivation of a receptor on the membrane, of the PGF2α receptor or elseof what is called the FP receptor. The FP receptor is one of the Gprotein-coupled receptors characterized by seven transmembrane domains.As well as the human FP receptor, it is also possible to clone the FPreceptors of mice and rats [Abramovitz et al., J. Biol. Chem. 1994,269:2632-2636; Sugimoto et al., J. Biol. Chem. 1994, 269:1356-1360;Kitanaka et al., Prostaglandins 1994, 48:31-41]. In humans there existtwo isoforms of the FP receptor, FPA and FPB. The FP receptor is theleast selective of the prostanoid receptors, since not only PGF2α butalso PGD2 and PGE2 bind to it with nanomolar affinities [Woodward etal., Pharmacol. Rev. 2011, 63:471-538]. Stimulation of the FP receptorleads primarily to Gq-dependent activation of phospholipase C, whichresults in release of calcium and activation of thediacylglycerol-dependent protein kinase C (PKC). The elevatedintracellular calcium level leads to calmodulin-mediated stimulation ofmyosin light-chain kinase (MLCK). As well as coupling to the G proteinGq, the FP receptor, via G12/G13, can also stimulate the Rho/Rho kinasesignal transduction cascade and, via Gi coupling, can alternativelystimulate the Raf/MEK/MAP signaling pathway [Woodward et al., Pharmacol.Rev. 2011, 63:471-538].

PGF2α is involved in the regulation of numerous physiological functions,for example ovarian functions, embryonal development, changes in theendometrium, uterine contraction and luteolysis, and in the induction ofcontractions and birth. PGF2α is also synthesized in epithelial cells inthe endometrium, where it stimulates cellular proliferation [Woodward etal., Pharmacol. Rev. 2011, 63:471-538]. In addition, PGF2α is a potentstimulator of smooth muscle constriction, vascular constriction andbronchoconstriction, and is involved in acute and chronic inflammatoryprocesses [Basu, Mol. Cells 2010, 30:383-391]. In the kidney, PGF2α isinvolved in water absorption, natriuresis and diuresis. In the eyes,PGF2α regulates intraocular pressure. PGF2α also plays an important rolein bone metabolism: Prostaglandin stimulates the sodium-dependenttransport of inorganic phosphate into osteoblasts and it promotes therelease of interleukin-6 and vascular endothelial growth factor (VEGF)in osteoblasts; in addition, PGF2α is a strong mitogen and a survivalfactor for osteoblasts [Agas et al., J. Cell Physiol. 2013, 228:25-29].Furthermore, it has been shown that PGF2α-FP receptor activation isinvolved in various cardiovascular dysfunctions, for example myocardialinfarction and hypertension [Zhang et al., Frontiers in Pharmacol. 2010,1:1-7]. More stable analogs of PGF2α have been developed for estrussynchronization and for influencing human reproductive functions, andalso for reduction of intraocular pressure for treatment of glaucoma[Basu, Mol. Cells 2010, 30:383-391].

In patients having idiopathic pulmonary fibrosis (IPF), it has beenshown that the stable PGF2α metabolite 15-ketodihydro-PGF2α issignificantly elevated in the plasma and that the level of15-ketodihydro-PGF2α correlates with functional parameters, for exampleforced vital capacity (FVC), the diffusion distance of carbon monoxidein the lung (DLCO) and the 6-minute walk test. In addition, arelationship between elevated plasma 15-ketodihydro-PGF2α and themortality of patients has been detected [Aihara et al., PLoS One 2013,8:1-6]. In accordance with this, it has also been shown that stimulationof human lung fibroblasts with naturally occurring silica dusts, whichin humans can lead to silicosis in the event of chronic inhalation andas a result to pulmonary fibrosis, brings about significant upregulationof PGF2α synthesis [O'Reilly et al., Am. J. Physiol. Lung Cell. Mol.Physiol. 2005, 288: L1010-L1016]. In bleomycin-induced pulmonaryfibrosis in mice, the elimination of the FP receptor by knockdown (FP−/−) led to a distinct reduction in pulmonary fibrosis compared towild-type mice [Oga et al., Nat. Med. 2009, 15:1426-1430]. In FP −/−mice, after administration of bleomycin, a significant reduction in thehydroxyproline content and reduced induction of profibrotic genes in thepulmonary tissue was observed. Moreover, lung function was distinctlyimproved in FP −/− mice compared to the wild-type mice. In humanpulmonary fibroblasts, PGF2α stimulates proliferation and collagenproduction via the FP receptor. Since this occurs independently of theprofibrotic mediator TGFβ, the PGF2α/FP receptor signaling cascadeconstitutes an independent route in the onset of pulmonary fibrosis [Ogaet al., Nat. Med. 2009, 15:1426-1430]. These findings show that the FPreceptor is a therapeutic target protein for treatment of IPF [Olman,Nat. Med. 2009, 15:1360-1361]. The involvement of PGF2α in the inductionof fibrotic lesions has also been shown in cardiac mouse fibroblasts[Ding et al., Int. J. Biochem. & Cell Biol. 2012, 44: 1031-1039], in ananimal model of scleroderma [Kanno et al., Arthritis Rheum. 2013, 65:492-502] and in synoviocytes from patients with gonarthrosis[Bastiaansen et al. Arthritis Rheum. 2013, 65: 2070-2080].

It is therefore assumed that the FP receptor plays an important role inmany disorders, injuries and pathological lesions whose etiology and/orprogression is associated with inflammatory events and/or proliferativeand fibroproliferative tissue and vessel remodeling. These mayespecially be disorders of and/or damage to the lung, the cardiovascularsystem or the kidney, or the disorder may be a blood disorder, aneoplastic disease or another inflammatory disorder.

Disorders of and damage to the lung which may be mentioned in thiscontext are in particular idiopathic pulmonary fibrosis, pulmonaryhypertension, bronchiolitis obliterans syndrome (BOS),chronic-obstructive pulmonary disease (COPD), asthma and cysticfibrosis. Disorders of and damage to the cardiovascular system in whichthe FP receptor is involved are, for example, tissue lesions followingmyocardial infarction and associated with heart failure. Renal disordersare, for example, renal insufficiency and kidney failure. An example ofa blood disorder is sickle cell anemia.

Examples of tissue degradation and remodeling in the event of neoplasticprocesses are the invasion of cancer cells into healthy tissue(formation of metastases) and neovascularization (neoangiogenesis).Other inflammatory diseases where the FP receptor plays a role are, forexample, arthrosis and multiple sclerosis.

Idiopathic fibrosis of the lung or idiopathic pulmonary fibrosis (IPF)is a progressive lung disease which, left untreated, results in deathwithin an average of 2.5 to 3.5 years after diagnosis. At the time ofdiagnosis, patients are usually more than 60 years old, men beingslightly more frequently affected than women. Onset of IPF is insidiousand characterized by increasing shortness of breath and a dry ticklycough. IPF is one of the group of idiopathic interstitial pneumonias(IIP), a heterogeneous group of pulmonary disorders which arecharacterized by fibrosis and inflammation of varying severity which canbe distinguished using clinical, imaging and fine tissue criteria.Within this group, idiopathic pulmonary fibrosis is of particularsignificance owing to its frequency and aggressive progression [Ley etal., Am. J. Respir. Crit. Care Med. 183, 431-440 (2011)]. IPF may eitheroccur sporadically or be hereditary. As yet, the causes are unknown.However, in recent years there have been numerous indications thatchronic damage of the alveolar epithelium leads to the release ofprofibrotic cytokines/mediators followed by increased fibroblastproliferation and increased collagen fiber formation, resulting in apatchy fibrosis and the typical honeycomb structure of the lung[Strieter et al., Chest 136, 1364-1370 (2009)]. The clinical sequelae offibrotization are a decrease in the elasticity of the pulmonary tissue,a reduced diffusing capacity and the development of severe hypoxia. Withregard to lung function, a corresponding worsening of the forced vitalcapacity (FVC) and the diffusing capacity (DLCO) can be detected.Essential and prognostically important comorbidities of IPF are acuteexacerbation and pulmonary hypertension [Beck et al., Pneumologe 10,105-111 (2013)]. The prevalence of pulmonary hypertension ininterstitial pulmonary disorders is 10-40% [Lettieri et al., Chest 129,746-752 (2006); Behr et al., Eur. Respir. J. 31, 1357-1367 (2008)].Currently, there is no curative treatment for IPF—except for lungtransplantation.

Pulmonary hypertension (PH) is a progressive lung disease which, leftuntreated, results in death within an average of 2.8 years afterdiagnosis. By definition, the mean pulmonary arterial pressure (mPAP) incase of chronic pulmonary hypertension is >25 mmHg at rest or >30 mmHgunder exertion (normal value <20 mmHg). The pathophysiology of pulmonaryhypertension is characterized by vasoconstriction and remodeling of thepulmonary vessels. In chronic PH, there is a neomuscularization ofprimarily unmuscularized lung vessels, and the circumference of thevascular musculature of the vessels already muscularized increases. Thisincreasing obliteration of the pulmonary circulation results inprogressive stress on the right heart, which leads to a reduced outputfrom the right heart and eventually ends in right heart failure [M.Humbert et al., J. Am. Coll. Cardiol. 2004, 43, 13S-24S]. Idiopathic (orprimary) pulmonary arterial hypertension (IPAH) is a very rare disorder,whereas secondary pulmonary hypertension (non-PAH PH, NPAHPH) is verycommon, and it is thought that the latter is currently the third mostcommon group of cardiovascular disorders after coronary heart diseaseand systemic hypertension [Naeije, in: A. J. Peacock et al. (Eds.),Pulmonary Circulation. Diseases and their treatment, 3^(rd) edition,Hodder Arnold Publ., 2011, p. 3]. Since 2008, pulmonary hypertension isclassified in accordance with the Dana Point classification into varioussub-groups according to the respective etiology [D. Montana and G.Simonneau, in: A. J. Peacock et al. (Eds.), Pulmonary Circulation.Diseases and their treatment, 3^(rd) edition, Hodder Arnold Publ., 2011,p. 197-206].

Despite all the advances in the therapy of PH there is as yet noprospect of cure of this serious disorder. Standard therapies availableon the market (for example prostacyclin analogs, endothelin receptorantagonists, phosphodiesterase inhibitors) are able to improve thequality of life, the exercise tolerance and the prognosis of thepatients. These are therapeutic principles which are administeredsystemically and act primarily hemodynamically by modulating vesseltone. The applicability of these medicaments is limited owing to sideeffects, some of which are serious, and/or complicated administrationforms. The period over which the clinical situation of the patients canbe improved or stabilized by specific monotherapy is limited (forexample owing to the development of tolerance). Eventually the therapyescalates and thus a combination therapy is applied, where a pluralityof medicaments must be given concurrently. Currently, these standardtherapeutics are approved only for the treatment of pulmonary arterialhypertension (PAH). In the case of secondary forms of PH such asPH-COPD, these therapeutic principles (for example sildenafil, bosentan)fail in clinical studies since, as a result of non-selectivevasodilation, they lead to a reduction (desaturation) of the arterialoxygen content in the patients. The probable reason for this is anunfavorable effect on the ventilation-perfusion adaptation in the lungin heterogeneous lung disorders owing to the systemic administration ofnon-selective vasodilators [I. Blanco et al., Am. J. Respir. Crit. CareMed. 2010, 181, 270-278; D. Stolz et al., Eur. Respir. J. 2008, 32,619-628].

Novel combination therapies are one of the most promising futuretherapeutic options for the treatment of pulmonary hypertension. In thisconnection, the finding of novel pharmacological mechanisms for thetreatment of PH is of particular interest [Ghofrani et al., Herz 2005,30, 296-302; E. B. Rosenzweig, Expert Opin. Emerging Drugs 2006, 11,609-619; T. Ito et al., Curr. Med. Chem. 2007, 14, 719-733]. Inparticular novel therapeutic approaches which can be combined with thetherapy concepts already on the market may form the basis of a moreefficient treatment and thus be of great advantage for the patients.

In the context of the present invention, the term “pulmonaryhypertension” includes both primary and secondary sub-forms (NPAHPH) asdefined according to the Dana Point classification in accordance withtheir respective etiology [D. Montana and G. Simonneau, in: A. J.Peacock et al. (Eds.), Pulmonary Circulation. Diseases and theirtreatment, 3^(rd) edition, Hodder Arnold Publ., 2011, pp. 197-206;Hoeper et al., J. Am. Coll. Cardiol., 2009, 54 (1), Suppl. S, p85-p96].These include in particular in group 1 pulmonary arterial hypertension(PAH), which, among others, embraces the idiopathic and the familialforms (IPAH and FPAH, respectively). Furthermore, PAH also embracespersistent pulmonary hypertension of the newborn and the associatedpulmonary arterial hypertension (APAH) associated with collagenoses,congenital systemic pulmonary shunt lesions, portal hypertension, HIVinfections, the intake of certain drugs and medicaments (for example ofappetite suppressants), with disorders having a significantvenous/capillary component such as pulmonary venoocclusive disorder andpulmonary capillary hemangiomatosis, or with other disorders such asdisorders of the thyroid, glycogen storage diseases, Gaucher disease,hereditary teleangiectasia, hemoglobinopathies, myeloproliferativedisorders and splenectomy. Group 2 of the Dana Point classificationcomprises PH patients having a causative left heart disorder, such asventricular, atrial or valvular disorders. Group 3 comprises forms ofpulmonary hypertension associated with a lung disorder, for example withchronic obstructive lung disease (COPD), interstitial lung disease(ILD), pulmonary fibrosis (IPF), and/or hypoxemia (e.g. sleep apneasyndrome, alveolar hypoventilation, chronic high-altitude sickness,hereditary deformities). Group 4 includes PH patients having chronicthrombotic and/or embolic disorders, for example in the case ofthromboembolic obstruction of proximal and distal pulmonary arteries(CTEPH) or non-thrombotic embolisms (e.g. as a result of tumordisorders, parasites, foreign bodies). Less common forms of pulmonaryhypertension, such as in patients suffering from sarcoidosis,histiocytosis X or lymphangiomatosis, are summarized in group 5.

The bronchiolitis obliterans syndrome (BOS) is a chronic rejectionreaction after a lung transplantation. Within the first five years aftera lung transplant about 50-60% of all patients are affected, and withinthe first nine years more than 90% of patients [Estenne et al., Am. J.Respir. Crit. Care Med. 166, 440-444 (2003)]. The cause of the diseasehas not been elucidated. In spite of numerous improvements in thetreatment of transplantation patients, the number of BOS cases hashardly changed over the last years. BOS is the most important long-termcomplication in lung transplantations and is considered to be the mainreason for the fact that survival rates are still markedly below thosefor other organ transplantations. BOS is an inflammatory event which isassociated with changes in the lung tissue affecting primarily the smallrespiratory passages. Damage and inflammatory changes of the epithelialcells and the subepithelial structures of the smaller respiratorypassages lead, owing to ineffective regeneration of the epithelium andaberrant tissue repair, to excessive fibroproliferation. There isscarring and finally destruction of the bronchi and also clots ofgranulation tissue in the small respiratory passages and alveolae,occasionally with vascular involvement. The diagnosis is based on thelung function. In BOS, there is a worsening of the FEV1 compared to theaverage of the two best values measured postoperatively. Currently,there is no curative treatment of BOS. Some of the patients showimprovements under intensified immunosuppression; patients not showingany response experience persistent deterioration, such thatretransplantation is indicated.

Chronic obstructive pulmonary disease (COPD) is a slowly progressingpulmonary disease characterized by an obstruction of respiratory flowwhich is caused by pulmonary emphysema and/or chronic bronchitis. Thefirst symptoms of the disease generally manifest themselves during thefourth or fifth decade of life. In the subsequent years of life,shortness of breath frequently becomes worse, and there are instances ofcoughing combined with copious and purulent sputum, and stenoticrespiration extending as far as breathlessness (dyspnea). COPD isprimarily a smokers' disease: smoking is the cause of 90% of all casesof COPD and of 80-90% of all COPD-related deaths. COPD is a big medicalproblem and constitutes the sixth most frequent cause of deathworldwide. Of people over the age of 45, about 4-6% are affected.Although the obstruction of the respiratory flow may only be partial andtemporal, COPD cannot be cured. Accordingly, the aim of treatment is toimprove the quality of life, to alleviate the symptoms, to prevent acuteworsening and to slow the progressive impairment of lung function.Existing pharmacotherapies, which have hardly changed over the last twoor three decades, are the use of bronchodilators to open blockedrespiratory passages, and in certain situations corticosteroids tocontrol the inflammation of the lung [P. J. Barnes, N. Engl. J. Med.343, 269-280 (2000)]. The chronic inflammation of the lung, caused bycigarette smoke or other irritants, is the driving force of thedevelopment of the disease. The basic mechanism comprises immune cellswhich, during the inflammatory reaction of the lung, release proteasesand various cytokines which cause pulmonary emphysema and remodeling ofthe bronchi.

It is an object of the present invention to identify and provide novelsubstances that are potent, chemically and metabolically stable,non-prostanoid antagonists of the FP receptor, and are suitable as suchfor treatment and/or prevention particularly of fibrotic andinflammatory disorders.

WO 95/32948-A1, WO 96/02509-A1 and WO 97/19926-A1, inter alia, disclose2-arylquinoline-4-carboxamides as NK₃ or dual NK₂/NK₃ antagonistssuitable for treatment of disorders of the lung and central nervoussystem. WO 2004/045614-A1 describes particular quinolinecarboxamides asglucokinase ligands for the treatment of diabetes. WO 2006/094237-A2discloses quinoline derivatives as sirtuin modulators which can be usedfor treatment of various kinds of disorders. WO 2011/009540-A2 describesbicyclic carboxamides having pesticidal action. WO 2011/153553-A2 claimsvarious bicyclic heteroaryl compounds as kinase inhibitors for thetreatment of neoplastic disorders in particular. EP 2 415 755-A1describes, inter alia, quinoline derivatives suitable for treatment ofdisorders associated with the activity of plasminogen activatorinhibitor 1 (PAI-1). WO 2013/074059-A2 details variousquinoline-4-carboxamide derivatives which can serve as inhibitors ofcytosine deaminases for boosting DNA transfection of cells. WO2013/164326-A1 discloses N,3-diphenylnaphthalene-1-carboxamides asagonists of the EP2 prostaglandin receptor for treatment of respiratorypathway disorders. WO 2014/117090-A1 describes various 2-arylquinolinederivatives as inhibitors of metalloenzymes. In the meantime, WO2015/094912-A1 has disclosed, inter alia, substitutedN,2-diphenylquinoline-4-carboxamide derivatives that are suitable asantagonists of the prostaglandin EP4 receptor for treatment of arthritisand associated states of pain.

The present invention provides compounds of the general formula (I)

-   R^(A) is hydrogen, halogen, pentafluorosulfanyl, cyano, nitro,    (C₁-C₄)-alkyl, hydroxyl, (C₁-C₄)-alkoxy, amino or a group of the    formula —NH—C(═O)—R⁶, —NH—C(═O)—NH—R⁶ or —S(═O)_(n)—R⁷,    -   where (C₁-C₄)-alkyl and (C₁-C₄)-alkoxy may be up to        trisubstituted by fluorine,    -   and in which    -   R⁶ is hydrogen or (C₁-C₄)-alkoxy which may be up to        trisubstituted by fluorine,    -   R⁷ is (C₁-C₄)-alkyl which may be substituted by hydroxyl,        methoxy or ethoxy or up to trisubstituted by fluorine,    -   and    -   n is the number 0, 1 or 2,-   D is C—R^(D) or N,-   E is C—R^(E) or N,-   G is C—R^(G) or N,    -   where not more than two of the ring members D, E and G at the        same time are N,    -   and in which    -   R^(D) and R^(E) are each independently hydrogen, fluorine,        chlorine, methyl, trifluoromethyl, methoxy or trifluoromethoxy,    -   and    -   R^(G) is hydrogen, fluorine, chlorine, bromine, methyl or        trifluoromethyl,-   Z is OH or a group of the formula —NH—R⁸, —NH—SO₂—R⁹ or    —NH—SO₂—NR^(10A)R^(10B), in which    -   R⁸ is hydrogen or (C₁-C₄)-alkoxy which may be up to        trisubstituted by fluorine,    -   R⁹ is (C₁-C₄)-alkoxy which may be up to trisubstituted by        fluorine, or phenyl,    -   and    -   R^(10A) and R^(10B) are each independently hydrogen or        (C₁-C₄)-alkyl which may be up to trisubstituted by fluorine,-   R¹ is halogen, trifluoromethoxy, (trifluoromethyl)sulfanyl,    pentafluorosulfanyl, (C₁-C₄)-alkyl, trimethylsilyl, cyclopropyl or    cyclobutyl,    -   where (C₁-C₄)-alkyl may be up to trisubstituted by fluorine    -   and    -   cyclopropyl and cyclobutyl may be up to disubstituted by        fluorine,-   R², R³ and R⁴ are each independently hydrogen, fluorine, chlorine,    methyl or trifluoromethyl,-   R⁵ is (C₁-C₄)-alkyl which may be up to trisubstituted by fluorine,    or is fluorine, chlorine, methoxy or cyclopropyl,-   and-   Ar is phenyl which may be mono- or disubstituted identically or    differently by fluorine and chlorine, or is pyridyl or thienyl,    and the N-oxides, salts, solvates, salts of the N-oxides and    solvates of the N-oxides and salts thereof.

Compounds of the invention are the compounds of the formula (I) and thesalts, solvates and solvates of the salts thereof, the compounds thatare encompassed by formula (I) and are of the formulae mentioned belowand the salts, solvates and solvates of the salts thereof and thecompounds that are encompassed by formula (I) and are cited below asworking examples and the salts, solvates and solvates of the saltsthereof if the compounds that are encompassed by formula (I) and arementioned below are not already salts, solvates and solvates of thesalts.

Compounds of the invention are likewise N-oxides of the compounds of theformula (I) and the salts, solvates and solvates of the salts thereof.

Preferred salts in the context of the present invention arephysiologically acceptable salts of the compounds of the invention. Alsoencompassed are salts which are not themselves suitable forpharmaceutical applications but can be used, for example, for theisolation, purification or storage of the compounds of the invention.

Physiologically acceptable salts of the compounds of the inventionespecially include the salts derived from conventional bases, by way ofexample and with preference alkali metal salts (e.g. sodium andpotassium salts), alkaline earth metal salts (e.g. calcium and magnesiumsalts), zinc salts and ammonium salts derived from ammonia or organicamines having 1 to 16 carbon atoms, by way of example and withpreference ethylamine, diethylamine, triethylamine,N,N-diisopropylethylamine, monoethanolamine, diethanolamine,triethanolamine, dimethylaminoethanol, diethylaminoethanol,tris(hydroxymethyl)aminomethane, choline, procaine, dicyclohexylamine,dibenzylamine, N-methylmorpholine, N-methylpiperidine, arginine, lysineand 1,2-ethylenediamine.

In addition, physiologically acceptable salts of the compounds of theinvention include acid addition salts of mineral acids, carboxylic acidsand sulfonic acids, for example salts of hydrochloric acid, hydrobromicacid, sulfuric acid, phosphoric acid, methanesulfonic acid,ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid,naphthalenedisulfonic acid, formic acid, acetic acid, trifluoroaceticacid, propionic acid, succinic acid, fumaric acid, maleic acid, lacticacid, tartaric acid, malic acid, citric acid, gluconic acid, benzoicacid and embonic acid.

Solvates in the context of the invention are described as those forms ofthe compounds of the invention which form a complex in the solid orliquid state by coordination with solvent molecules. Hydrates are aspecific form of the solvates in which the coordination is with water.Solvates preferred in the context of the present invention are hydrates.

The compounds of the invention may, depending on their structure, existin different stereoisomeric forms, i.e. in the form of configurationalisomers or else, if appropriate, as conformational isomers (enantiomersand/or diastereomers, including those in the case of atropisomers). Thepresent invention therefore encompasses the enantiomers anddiastereomers, and the respective mixtures thereof. It is possible toisolate the stereoisomerically homogeneous constituents from suchmixtures of enantiomers and/or diastereomers in a known manner.Preference is given to employing chromatographic methods for thispurpose, especially HPLC chromatography on achiral or chiral separationphases. In the case of carboxylic acids as intermediates or endproducts, separation is alternatively also possible via diastereomericsalts using chiral amine bases.

If the compounds of the invention can occur in tautomeric forms, thepresent invention encompasses all the tautomeric forms.

The present invention also encompasses all suitable isotopic variants ofthe compounds of the invention. An isotopic variant of a compound of theinvention is understood here to mean a compound in which at least oneatom within the compound of the invention has been exchanged for anotheratom of the same atomic number, but with a different atomic mass fromthe atomic mass which usually or predominantly occurs in nature.Examples of isotopes which can be incorporated into a compound of theinvention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus,sulfur, fluorine, chlorine, bromine and iodine, such as ²H (deuterium),³H (tritium), ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³²P, ³³P, ³³S, ³⁴S, ³⁵S, ³⁶S,1⁸F, ³⁶Cl, ⁸²Br, ¹²³I, ¹²⁴I, ¹²⁹I and ¹³¹I. Particular isotopic variantsof a compound of the invention, especially those in which one or moreradioactive isotopes have been incorporated, may be beneficial, forexample, for the examination of the mechanism of action or of the activecompound distribution in the body; due to the comparatively easypreparability and detectability, especially compounds labeled with ³H or¹⁴C isotopes are suitable for this purpose. In addition, theincorporation of isotopes, for example of deuterium, can lead toparticular therapeutic benefits as a consequence of greater metabolicstability of the compound, for example an extension of the half-life inthe body or a reduction in the active dose required; such modificationsof the compounds of the invention may therefore possibly also constitutea preferred embodiment of the present invention. Isotopic variants ofthe compounds of the invention can be prepared by commonly usedprocesses known to those skilled in the art, for example by the methodsdescribed further down and the procedures described in the workingexamples, by using corresponding isotopic modifications of therespective reagents and/or starting compounds.

The present invention additionally also encompasses prodrugs of thecompounds of the invention. The term “prodrugs” refers here to compoundswhich may themselves be biologically active or inactive, but areconverted while present in the body, for example by a metabolic orhydrolytic route, to compounds of the invention.

The present invention comprises as prodrugs in particular hydrolyzableester derivatives of the inventive carboxylic acids of the formula (I)[with Z=OH]. These are understood to mean esters which can be hydrolyzedto the free carboxylic acids, as the main biologically active compounds,in physiological media under the conditions of the biological testsdescribed hereinbelow and in particular in vivo by an enzymatic orchemical route. (C₁-C₄)-Alkyl esters, in which the alkyl group can bestraight-chain or branched, are preferred as such esters. Particularpreference is given to methyl, ethyl or tert-butyl esters.

In the context of the present invention, unless specified otherwise, thesubstituents are defined as follows:

In the context of the invention, (C₁-C₄)-alkyl is a straight-chain orbranched alkyl radical having 1 to 4 carbon atoms. By way of example andwith preference, mention may be made of the following: methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

(C₁-C₄)-Alkoxy in the context of the invention is a straight-chain orbranched alkoxy radical having 1 to 4 carbon atoms. By way of exampleand with preference, mention may be made of the following: methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy andtert-butoxy.

Halogen in the context of the invention includes fluorine, chlorine,bromine and iodine. Preference is given to chlorine, fluorine orbromine, particular preference to fluorine or chlorine.

In the context of the present invention, all radicals which occur morethan once are defined independently of one another. When radicals in thecompounds of the invention are substituted, the radicals may be mono- orpolysubstituted, unless specified otherwise. Substitution by onesubstituent or by two identical or different substituents is preferred.Particular preference is given to substitution by one substituent.

A particular embodiment of the present invention comprises compounds ofthe formula (I) in which

-   R^(A) is hydrogen, fluorine, chlorine, bromine, cyano, nitro,    methyl, trifluoromethyl, hydroxyl, methoxy, trifluoromethoxy or a    group of the formula —S(═O)_(n)—R⁷ in which    -   R⁷ is methyl or trifluoromethyl,    -   and    -   n is the number 0 or 2,-   D is C—R^(D) or N, in which    -   R^(D) is hydrogen or fluorine,-   E is C—H-   and-   G is C—R^(G) or N, in which    -   R^(G) is hydrogen, fluorine or chlorine,        and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention encompassescompounds of the formula (I) in which

-   R^(A) is fluorine, chlorine, bromine, cyano, methyl,    trifluoromethyl, methoxy, trifluoromethoxy or a group of the formula    —S(═O)_(n)—R⁷ in which    -   R⁷ is methyl or trifluoromethyl,    -   and    -   n is the number 0, 1 or 2,-   D is C—H,-   E is C—H-   and-   G is C—R^(G) or N, in which    -   R^(G) is hydrogen, fluorine or chlorine,        and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention encompassescompounds of the formula (I) in which

Z is OH,

and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention encompassescompounds of the formula (I) in which

-   R¹ is chlorine, bromine, iodine, methyl, ethyl, isopropyl,    trifluoromethyl, trifluoromethoxy, (trifluoromethyl)sulfanyl,    pentafluorosulfanyl or trimethylsilyl,-   R² and R³ are each hydrogen-   and-   R⁴ is hydrogen, fluorine or chlorine,    and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention encompassescompounds of the formula (I) in which

-   R¹ is bromine-   and-   R², R³ and R⁴ are each hydrogen,    and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention encompassescompounds of the formula (I) in which

-   R¹ and R⁴ are each chlorine-   and-   R² and R³ are each hydrogen,    and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention encompassescompounds of the formula (I) in which

-   R⁵ is methyl,    and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention encompassescompounds of the formula (I) in which

-   Ar is phenyl which may be monosubstituted by fluorine, or pyridyl,    and the salts, solvates and solvates of the salts thereof.

Preference is given in the context of the present invention to compoundsof the formula (I) in which

-   R^(A) is hydrogen, fluorine, chlorine, bromine, cyano, methyl,    trifluoromethyl, methoxy, trifluoromethoxy or a group of the formula    —S(═O)_(n)—R⁷ in which    -   R⁷ is methyl or trifluoromethyl,    -   and    -   n is the number 0 or 2,-   D is C—R^(D) or N, in which    -   R^(D) is hydrogen or fluorine,-   E is C—H,-   G is C—R^(G) or N, in which    -   R^(G) is hydrogen, fluorine or chlorine,-   Z is OH,-   R¹ is chlorine, bromine, iodine, methyl, ethyl, isopropyl,    trifluoromethyl, trifluoromethoxy, (trifluoromethyl)sulfanyl,    pentafluorosulfanyl or trimethylsilyl,-   R² and R³ are each hydrogen,-   R⁴ is hydrogen, fluorine or chlorine,-   R⁵ is methyl, chlorine or cyclopropyl,-   and-   Ar is phenyl which may be monosubstituted by fluorine, or pyridyl,    and the salts, solvates and solvates of the salts thereof.

In the context of the present invention, particular preference is givento compounds of the formula (I) in which

-   R^(A) is fluorine, chlorine, cyano, methyl, trifluoromethyl,    methoxy, trifluoromethoxy or a group of the formula —S(═O)_(n)—R⁷ in    which    -   R⁷ is methyl or trifluoromethyl,    -   and    -   n is the number 0 or 2,-   D is C—H,-   E is C—H,-   G is C—R^(G) or N, in which    -   R^(G) is hydrogen, fluorine or chlorine,-   Z is OH,-   R¹ is chlorine, bromine, methyl, trifluoromethyl or trimethylsilyl,-   R² and R³ are each hydrogen,-   R⁴ is hydrogen or chlorine,-   R⁵ is methyl,-   and-   Ar is phenyl which may be monosubstituted by fluorine, or 4-pyridyl,    and the salts, solvates and solvates of the salts thereof.

The individual radical definitions specified in the respectivecombinations or preferred combinations of radicals are, independently ofthe respective combinations of the radicals specified, also replaced asdesired by radical definitions of other combinations.

Very particular preference is given to combinations of two or more ofthe abovementioned preferred ranges.

The invention further provides a process for preparing the compounds ofthe invention, characterized in that a compound of the formula (II)

in which R¹, R², R³, R⁴, R⁵ and Ar have the definitions given above,with activation of the carboxylic acid function is coupled with an aminecompound of the formula (III)

in which R^(A), D, E and G have the definitions given aboveandT is (C₁-C₄)-alkyl or benzylto give a compound of the formula (IV)

in which R^(A), D, E, G, R¹, R², R³, R⁴, R⁵, Ar and T have thedefinitions given above,and then the ester radical T is eliminated to give the inventivecarboxylic acid of the formula (I-A)

in which R^(A), D, E, G, R¹, R², R³, R⁴, R⁵ and Ar have the definitionsgiven above,and if necessary the carboxylic acid (I-A) is converted to thecorresponding acid chloride of the formula (V)

in which R^(A), D, E, G, R¹, R², R³, R⁴, R⁵ and Ar have the definitionsgiven above,and the latter is subsequently reacted with a compound of the formula(VI)

H₂N—R⁸  (VI)

in which R⁸ has the definition given aboveto give the inventive carboxamide of the formula (I-B)

in which R^(A), D, E, G, R¹, R², R³, R⁴, R⁵, R⁸ and Ar have thedefinitions given above,and the compounds of the formulae (I-A) and (I-B) thus obtained areoptionally converted with the appropriate (i) solvents and/or (ii) basesor acids to the solvates, salts and/or solvates of the salts thereof.

The coupling reaction (II)+(III)→(IV) [amide formation] can be effectedeither by a direct route with the aid of a condensing or activatingagent or via the intermediate stage of a carbonyl chloride or carbonylimidazolide obtainable from (II).

Suitable condensing or activating agents of this kind are, for example,carbodiimides such as N,N′-diethyl-, N,N′-dipropyl-, N,N′-diisopropyl-,N,N′-dicyclohexylcarbodiimide (DCC) orN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC),phosgene derivatives such as N,N′-carbonyldiimidazole (CDI) or isobutylchloroformate, 1,2-oxazolium compounds such as2-ethyl-5-phenyl-1,2-oxazolium 3-sulfate or2-tert-butyl-5-methylisoxazolium perchlorate, acylamino compounds suchas 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, α-chlorenamines suchas 1-chloro-N,N,2-trimethylprop-1-en-1-amine, 1,3,5-triazine derivativessuch as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholiniumchloride, phosphorus compounds such as n-propanephosphonic anhydride(PPA), diethyl cyanophosphonate, diphenylphosphoryl azide (DPPA),bis(2-oxo-3-oxazolidinyl)phosphoryl chloride,benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphateor benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate(PyBOP), or uronium compounds such asO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU),O-(1H-6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (TCTU),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) or2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethyluronium tetrafluoroborate(TPTU), optionally in combination with further auxiliaries such as1-hydroxybenzotriazole (HOBt) or N-hydroxysuccinimide (HOSu), and, asbases, alkali metal carbonates, e.g. sodium or potassium carbonate, ortertiary amine bases such as triethylamine, N-methylmorpholine (NMM),N-methylpiperidine (NMP), N,N-diisopropylethylamine, pyridine or4-N,N-dimethylaminopyridine (DMAP). The preferred condensing oractivating agent used is 1-chloro-N,N,2-trimethylprop-1-en-1-amine incombination with pyridine orO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) in combination withN,N-diisopropylethylamine.

In the case of a two-stage reaction regime via the carbonyl chlorides orcarbonyl imidazolides obtainable from (II), the coupling with the aminecomponent (III) is conducted in the presence of a customary base, forexample sodium carbonate or potassium carbonate, triethylamine,N,N-diisopropylethylamine, N-methylmorpholine (NMM), N-methylpiperidine(NMP), pyridine, 2,6-dimethylpyridine, 4-N,N-dimethylaminopyridine(DMAP), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),1,5-diazabicyclo[4.3.0]non-5-ene (DBN), sodium methoxide or potassiummethoxide, sodium ethoxide or potassium ethoxide, sodium tert-butoxideor potassium tert-butoxide, or sodium hydride or potassium hydride. Thebase used for the coupling in the case of the carbonyl chlorides ispreferably pyridine, and in the case of carbonyl imidazolides preferablypotassium tert-butoxide or sodium hydride.

Inert solvents for the coupling reactions mentioned are—according to themethod used—for example ethers such as diethyl ether, diisopropyl ether,methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane,1,2-dimethoxyethane or bis(2-methoxyethyl) ether, hydrocarbons such asbenzene, toluene, xylene, pentane, hexane or cyclohexane,halohydrocarbons such as dichloromethane, trichloromethane, carbontetrachloride, 1,2-dichloroethane, trichloroethylene or chlorobenzene,or polar aprotic solvents such as acetone, methyl ethyl ketone, ethylacetate, acetonitrile, butyronitrile, pyridine, dimethyl sulfoxide(DMSO), N,N-dimethylformamide (DMF), N,N′-dimethylpropyleneurea (DMPU)or N-methylpyrrolidinone (NMP). It is also possible to use mixtures ofsuch solvents. Preference is given to using dichloromethane,tetrahydrofuran, N,N-dimethylformamide or mixtures of these solvents.The couplings are generally conducted within a temperature range from−20° C. to +60° C., preferably at 0° C. to +40° C.

The preferred coupling method is the reaction of a carbonyl imidazolidederived from (II) with the amine compound (III).

The carbonyl imidazolides themselves are obtainable by known methods byreaction of (II) with N,N′-carbonyldiimidazole (CDI) at elevatedtemperature (+60° C. to +150° C.) in a correspondingly relativelyhigh-boiling solvent such as N,N-dimethylformamide (DMF). Thepreparation of the carbonyl chlorides is accomplished in a customarymanner by treating (II) with thionyl chloride or oxalyl chloride in aninert solvent such as dichloromethane.

The detachment of the ester group T in process step (IV)→(I-A) isconducted by customary methods, by treating the ester in an inertsolvent with an acid or a base, with conversion of the salt of thecarboxylic acid initially formed in the latter variant to the freecarboxylic acid by subsequent treatment with acid. In the case of thetert-butyl esters, the ester cleavage is preferably effected with anacid. Methyl and ethyl ester are preferably cleaved using a base. Benzylesters can alternatively also be cleaved by hydrogenation(hydrogenolysis) in the presence of a suitable catalyst, for examplepalladium on activated carbon.

Suitable inert solvents for these reactions are water and the organicsolvents customary for ester cleavage. These include in particularalcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanolor tert-butanol, ethers such as diethyl ether, tetrahydrofuran,1,4-dioxane or 1,2-dimethoxyethane, or other solvents such asdichloromethane, acetonitrile, N,N-dimethylformamide or dimethylsulfoxide. It is equally possible to use mixtures of these solvents. Inthe case of a basic ester hydrolysis, preference is given to usingmixtures of water with tetrahydrofuran, 1,4-dioxane, methanol and/orethanol. Preference is given to using dichloromethane in the case of thereaction with trifluoroacetic acid, and 1,4-dioxane in the case of thereaction with hydrogen chloride, in each case under anhydrousconditions.

Suitable bases for a hydrolysis reaction are the customary inorganicbases. These especially include alkali metal or alkaline earth metalhydroxides, for example lithium hydroxide, sodium hydroxide, potassiumhydroxide or barium hydroxide, or alkali metal or alkaline earth metalcarbonates, such as sodium carbonate, potassium carbonate or calciumcarbonate. Preference is given to using lithium hydroxide or sodiumhydroxide.

Suitable acids for the ester hydrolysis are generally sulfuric acid,hydrogen chloride/hydrochloric acid, hydrogen bromide/hydrobromic acid,phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulfonicacid, methanesulfonic acid or trifluoromethanesulfonic acid, or mixturesthereof, optionally with addition of water. Preference is given to usinghydrogen chloride or trifluoroacetic acid.

The ester cleavage is generally conducted within a temperature rangefrom −20° C. to +100° C., preferably at 0° C. to +80° C.

The acid chloride (V) is prepared in a customary manner by treating thecarboxylic acid (I-A) with oxalyl chloride or thionyl chloride in aninert solvent such as dichloromethane, trichloromethane or1,2-dichloroethane, optionally with use of a small amount ofN,N-dimethylformamide as catalyst.

The reaction is generally conducted at a temperature of 0° C. to +30° C.

The subsequent amide formation in process step (V)+(VI)→(I-B) is usuallyeffected in the presence of a relatively large excess of the aminecomponent (VI). Alternatively, it is also possible to use a standardtertiary amine base as auxiliary base, for example triethylamine,N,N-diisopropylethylamine, N-methylmorpholine (NMM), N-methylpiperidine(NMP), pyridine, 2,6-dimethylpyridine or 4-N,N-dimethylaminopyridine(DMAP).

Inert solvents for this reaction are, for example, ethers such asdiethyl ether, diisopropyl ether, methyl tert-butyl ether,tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane or bis(2-methoxyethyl)ether, hydrocarbons such as benzene, toluene, xylene, pentane, hexane orcyclohexane, halohydrocarbons such as dichloromethane, trichloromethane,carbon tetrachloride, 1,2-dichloroethane, trichloroethylene orchlorobenzene, polar aprotic solvents such as acetone, methyl ethylketone, ethyl acetate, acetonitrile, butyronitrile, pyridine, dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF),N,N′-dimethylpropyleneurea (DMPU) or N-methylpyrrolidinone (NMP), orelse water. It is likewise possible to use mixtures of such solvents.Preference is given to using water or a mixture of water withtetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane or acetone. Thereaction is generally conducted at a temperature of 0° C. to +40° C.

Inventive compounds of the formula (I) in which Z is a group of theformula —NH—SO₂—R⁹ or —NH—SO₂—NR^(10A)R^(10B) can be obtained in analogyto the above-described amide formation (V)+(VI)→(I-B) by base-mediatedreaction of the acid chloride (V) with a compound of the formula (VI-A)or (VI-B)

in which R⁹, R^(20A) and R^(10B) have the definitions given above. Thereaction is preferably effected using sodium hydride as base intetrahydrofuran or N,N-dimethylformamide as inert solvent at atemperature of 0° C. to +50° C.

Further inventive compounds of the formula (I) can, if appropriate, alsobe prepared by transformations of functional groups of individualradicals or substituents, especially those listed under R^(A), R¹ andR⁵, proceeding from other compounds of the formula (I) or precursorsthereof obtained by the above processes. These transformations areconducted by customary methods familiar to the person skilled in the artand include, for example, reactions such as nucleophilic orelectrophilic substitution reactions, transition-metal-mediated couplingreactions, preparation and addition reactions of metal organyls (e.g.Grignard compounds or lithium organyls), oxidation and reductionreactions, hydrogenation, halogenation (e.g. fluorination, bromination),dehalogenation, amination, alkylation and acylation, the formation ofcarboxylic esters, carboxamides and sulfonamides, ester cleavage andhydrolysis, and the introduction and removal of temporary protectinggroups.

Depending on their respective substitution pattern, the compounds of theformula (II) can be prepared by, in analogy to processes known from theliterature, reacting either

[A] an isatin derivative of the formula (VII)

-   -   in which R¹, R², R³ and R⁴ have the definitions given above    -   in an acid- or base-mediated condensation reaction with a        ketomethylene compound of the formula (VIII)

-   -   in which R⁵ and Ar have the definitions given above    -   to give the compound of the formula (II)

-   -   in which R¹, R², R³, R⁴, R⁵ and Ar have the definitions given        above,        or        [B] an ortho-aminophenylacetic ester of the formula (IX)

-   -   in which R¹ has the definition given above    -   in an acid-induced condensation reaction with a diketo compound        of the formula (X)

-   -   in which R⁵ and Ar have the definitions given above    -   to give a compound of the formula (II-A)

-   -   in which R¹, R⁵ and Ar have the definitions given above.

The condensation of the isatin derivative (VII) with the ketomethylenecompound (VIII) to give the quinoline-4-carboxylic acid (II) in variant[A] can be achieved by heating the reactants in the presence of anaqueous acid, such as sulfuric acid or concentrated hydrochloric acid,or in the presence of an aqueous base, such as sodium hydroxide orpotassium hydroxide solution. In the case of use of an acid, preferenceis given to using acetic acid as solvent for the reaction; in the caseof a basic reaction regime, preference is given to using an alcoholicsolvent such as methanol or ethanol. The condensation is generallyconducted within a temperature range from +70° C. to +120° C. [cf., forexample, K. Lackey and D. D. Sternbach, Synthesis, 993-997 (1993); A. N.Boa et al., Bioorg. Med. Chem. 13 (6), 1945-1967 (2005)].

The condensation reaction according to variant [B] to give thequinoline-4-carboxylic acid (II-A) is effected in an analogous manner byheating the ortho-aminophenylacetic ester (IX) and the diketone (X) withaqueous acid, especially concentrated hydrochloric acid. The inertsolvent used for the reaction here too is preferably acetic acid.

The ortho-aminophenylacetic ester (IX) itself can be obtained inaccordance with a process described in the literature, by base-mediatedreaction of the α-chloroacetic ester (XI)

with the nitrophenyl derivative (XII)

in which R¹ has the definition given aboveto give the ortho-nitrophenylacetic ester (XIII)

in which R¹ has the definition given above,and subsequently reducing the nitro group, for example by catalytichydrogenation [cf. P. Beier et al., J. Org. Chem. 76, 4781-4786 (2011)].

The compounds of the formula (III) are commercially available or theirpreparation is described in the literature, or they can be preparedproceeding from other commercially available compounds by methods knownin the literature that are familiar to those skilled in the art.Examples of these are shown in the reaction schemes which follow.Detailed procedures and further literature references can also be foundin the experimental section, in the section on the preparation of thestarting compounds and intermediates.

The compounds of the formulae (VI), (VI-A), (VI-B), (VII), (VIII), (X),(XI) and (XII) are likewise commercially available or described as suchin the literature, or they can be prepared in a simple manner proceedingfrom other commercially available compounds in analogy to methods knownfrom the literature.

The preparation of the compounds of the invention can be illustrated byway of example by the following reaction schemes:

The compounds of the invention have valuable pharmacological propertiesand can be used for prevention and treatment of diseases in humans andanimals.

The compounds of the invention are potent, chemically and metabolicallystable antagonists of the FP receptor and are therefore suitable fortreatment and/or prevention of disorders and pathological processes,especially those where the FP receptor is involved in the course of aninflammatory event and/or tissue or vessel reconstruction.

In the context of the present invention, these especially includedisorders such as the group of the interstitial idiopathic pneumoniaswhich includes idiopathic pulmonary fibrosis (IPF), acute interstitialpneumonia, non-specific interstitial pneumonias, lymphoid interstitialpneumonias, respiratory bronchiolitis with interstitial lung disease,cryptogenic organizing pneumonias, desquamative interstitial pneumoniasand non-classifiable idiopathic interstitial pneumonias, furthermoregranulomatous interstitial lung diseases, interstitial lung diseases ofknown etiology and other interstitial lung diseases of unknown etiology,pulmonary arterial hypertension (PAH) and other forms of pulmonaryhypertension (PH), bronchiolitis obliterans syndrome (BOS),chronic-obstructive pulmonary disease (COPD), pulmonary sarcoidosis,acute respiratory distress syndrome (ARDS), acute lung injury (ALI),alpha-1-antitrypsin deficiency (AATD), pulmonary emphysema (for examplepulmonary emphysema induced by cigarette smoke), cystic fibrosis (CF),inflammatory and fibrotic disorders of the kidney, chronic intestinalinflammations (IBD, Crohn's disease, ulcerative colitis), peritonitis,peritoneal fibrosis, rheumatoid disorders, multiple sclerosis,inflammatory and fibrotic skin disorders, sickle cell anemia andinflammatory and fibrotic eye disorders.

The compounds of the invention can additionally be used for treatmentand/or prevention of asthmatic disorders of varying severity withintermittent or persistent characteristics (refractive asthma, bronchialasthma, allergic asthma, intrinsic asthma, extrinsic asthma, medicament-or dust-induced asthma), of various forms of bronchitis (chronicbronchitis, infectious bronchitis, eosinophilic bronchitis), ofbronchiectasis, pneumonia, farmer's lung and related disorders, coughsand colds (chronic inflammatory cough, iatrogenic cough), inflammationof the nasal mucosa (including medicament-related rhinitis, vasomotoricrhinitis and seasonal allergic rhinitis, for example hay fever) and ofpolyps.

In addition, the compounds of the invention can be used for treatmentand/or prevention of cardiovascular disorders such as, for example, highblood pressure (hypertension), heart failure, coronary heart disease,stable and unstable angina pectoris, renal hypertension, peripheral andcardiac vascular disorders, arrhythmias, atrial and ventriculararrhythmias and impaired conduction such as, for example,atrioventricular blocks degrees I-III, supraventricular tachyarrhythmia,atrial fibrillation, atrial flutter, ventricular fibrillation,ventricular flutter, ventricular tachyarrhythmia, Torsade de pointestachycardia, atrial and ventricular extrasystoles, AV-junctionalextrasystoles, sick sinus syndrome, syncopes, AV-nodal re-entrytachycardia, Wolff-Parkinson-White syndrome, acute coronary syndrome(ACS), autoimmune cardiac disorders (pericarditis, endocarditis,valvolitis, aortitis, cardiomyopathies), boxer cardiomyopathy,aneurysms, shock such as cardiogenic shock, septic shock andanaphylactic shock, furthermore for the treatment and/or prophylaxis ofthromboembolic disorders and ischemias such as myocardial ischemia,myocardial infarction, stroke, cardiac hypertrophy, transient andischemic attacks, preeclampsia, inflammatory cardiovascular disorders,spasms of the coronary arteries and peripheral arteries, edema formationsuch as, for example, pulmonary edema, cerebral edema, renal edema oredema caused by heart failure, peripheral circulatory disturbances,reperfusion damage, arterial and venous thromboses, microalbuminuria,myocardial insufficiency, endothelial dysfunction, micro- andmacrovascular damage (vasculitis), and also to prevent restenoses, forexample after thrombolysis therapies, percutaneous transluminalangioplasties (PTA), percutaneous transluminal coronary angioplasties(PTCA), heart transplants and bypass operations.

In the context of the present invention, the term “heart failure”encompasses both acute and chronic forms of heart failure, and alsospecific or related disease types thereof, such as acute decompensatedheart failure, right heart failure, left heart failure, global failure,ischemic cardiomyopathy, dilatative cardiomyopathy, hypertrophiccardiomyopathy, idiopathic cardiomyopathy, diabetic cardiomyopathy,congenital heart defects, heart valve defects, heart failure associatedwith heart valve defects, mitral valve stenosis, mitral valveinsufficiency, aortic valve stenosis, aortic valve insufficiency,tricuspid valve stenosis, tricuspid valve insufficiency, pulmonary valvestenosis, pulmonary valve insufficiency, combined heart valve defects,myocardial inflammation (myocarditis), chronic myocarditis, acutemyocarditis, viral myocarditis, diabetic heart failure, alcoholiccardiomyopathy, cardiac storage disorders and diastolic and systolicheart failure. The compounds of the invention are also suitable fortreatment and/or prevention of renal disorders, in particular renalinsufficiency and kidney failure. In the context of the presentinvention, the terms “renal insufficiency” and “kidney failure”encompass both acute and chronic manifestations thereof and alsounderlying or related renal disorders such as renal hypoperfusion,intradialytic hypotension, obstructive uropathy, glomerulopathies,glomerulonephritis, acute glomerulonephritis, glomerulosclerosis,tubulointerstitial diseases, nephropathic disorders such as primary andcongenital kidney disease, nephritis, immunological kidney disorderssuch as kidney transplant rejection and immunocomplex-induced kidneydisorders, nephropathy induced by toxic substances, nephropathy inducedby contrast agents, diabetic and non-diabetic nephropathy,pyelonephritis, renal cysts, nephrosclerosis, hypertensivenephrosclerosis and nephrotic syndrome which can be characterizeddiagnostically, for example by abnormally reduced creatinine and/orwater excretion, abnormally elevated blood concentrations of urea,nitrogen, potassium and/or creatinine, altered activity of renalenzymes, for example glutamyl synthetase, altered urine osmolarity orurine volume, elevated microalbuminuria, macroalbuminuria, lesions onglomerulae and arterioles, tubular dilatation, hyperphosphatemia and/orneed for dialysis. The present invention also encompasses the use of thecompounds of the invention for treatment and/or prevention of sequelaeof renal insufficiency, for example hypertension, pulmonary edema, heartfailure, uremia, anemia, electrolyte disturbances (for examplehyperkalemia, hyponatremia) and disturbances in bone and carbohydratemetabolism.

In addition, the compounds of the invention are suitable for treatmentand/or prevention of disorders of the urogenital system, for examplebenign prostate syndrome (BPS), benign prostate hyperplasia (BPH),benign prostate enlargement (BPE), bladder outlet obstruction (BOO),lower urinary tract syndromes (LUTS), neurogenic overactive bladder(OAB), incontinence, for example mixed urinary incontinence, urgeurinary incontinence, stress urinary incontinence or overflow urinaryincontinence (MUI, UUI, SUI, OUI), pelvic pain, and also erectiledysfunction and female sexual dysfunction.

The compounds of the invention can also be used for treatment ofdisorders of the female reproductive system, such as uterine myoma,endometriosis, dysmenorrhea and premature contractions. In addition,they are suitable for prophylaxis or treatment of hirsutism orhypertrichosis.

In addition, the compounds of the invention have antiinflammatory actionand can therefore be used as antiinflammatory agents for the treatmentand/or prevention of sepsis (SIRS), multiple organ failure (MODS, MOF),inflammatory disorders of the kidney, chronic intestinal inflammations(IBD, Crohn's disease, ulcerative colitis), pancreatitis, peritonitis,cystitis, urethritis, prostatitis, epidimytitis, oophoritis,salpingitis, vulvovaginitis, rheumatoid disorders, osteoarthritis,inflammatory disorders of the central nervous system, multiplesclerosis, infammatory skin disorders and inflammatory eye disorders.

The compounds of the invention are also suitable for treatment and/orprevention of fibrotic disorders of the internal organs, for example thelung, the heart, the kidney, the bone marrow and in particular theliver, and also dermatological fibroses and fibrotic eye disorders. Inthe context of the present invention, the term “fibrotic disorders”includes in particular disorders such as hepatic fibrosis, cirrhosis ofthe liver, pulmonary fibrosis, endomyocardial fibrosis, nephropathy,glomerulonephritis, interstitial renal fibrosis, fibrotic damageresulting from diabetes, bone marrow fibrosis, peritoneal fibrosis andsimilar fibrotic disorders, scleroderma, morphea, keloids, hypertrophicscarring, naevi, diabetic retinopathy, proliferative vitroretinopathyand disorders of the connective tissue (for example sarcoidosis). Thecompounds of the invention can likewise be used for promotion of woundhealing, for controlling postoperative scarring, for example followingglaucoma operations and cosmetically for ageing or keratinized skin.

The compounds of the invention can also be used for treatment and/orprevention of anemias such as hemolytic anemias, in particularhemoglobinopathies such as sickle cell anemia and thalassemias,megaloblastic anemias, iron deficiency anemias, anemias owing to acuteblood loss, displacement anemias and aplastic anemias.

Moreover, the compounds of the invention are suitable for treatment ofcancers, for example skin cancer, brain tumors, breast cancer, bonemarrow tumors, leukemias, liposarcomas, carcinomas of thegastrointestinal tract, of the liver, the pancreas, the lung, thekidney, the ureter, the prostate and the genital tract and also ofmalignant tumors of the lymphoproliferative system, for exampleHodgkin's and non-Hodgkin's lymphoma.

In addition, the compounds of the invention can be used for treatmentand/or prevention of arteriosclerosis, impaired lipid metabolism anddyslipidemias (hypolipoproteinemia, hypertriglyceridemias,hyperlipidemia, combined hyperlipidemias, hypercholesterolemia,abetalipoproteinemia, sitosterolemia), xanthomatosis, Tangier disease,adiposity, obesity, metabolic disorders (metabolic syndrome,hyperglycemia, insulin-dependent diabetes, non-insulin-dependentdiabetes, gestational diabetes, hyperinsulinemia, insulin resistence,glucose intolerance and diabetic sequelae, such as retinopathy,nephropathy and neuropathy), of disorders of the gastrointestinal tractand the abdomen (glossitis, gingivitis, periodontitis, esophagitis,eosinophilic gastroenteritis, mastocytosis, Crohn's disease, colitis,proctitis, anus pruritis, diarrhea, celiac disease, hepatitis, hepaticfibrosis, cirrhosis of the liver, pancreatitis and cholecystitis), ofdisorders of the central nervous system and neurodegenerative disorders(stroke, Alzheimer's disease, Parkinson's disease, dementia, epilepsy,depressions, multiple sclerosis), immune disorders, thyroid disorders(hyperthyreosis), skin disorders (psoriasis, acne, eczema,neurodermitis, various forms of dermatitis, for example dermatitisabacribus, actinic dermatitis, allergic dermatitis, ammonia dermatitis,facticial dermatitis, autogenic dermatitis, atopic dermatitis,dermatitis calorica, dermatitis combustionis, dermatitis congelationis,dermatitis cosmetica, dermatitis escharotica, exfoliative dermatitis,dermatitis gangraenose, stasis dermatitis, dermatitis herpetiformis,lichenoid dermatitis, dermatitis linearis, dermatitis maligna, medicinaleruption dermatitis, dermatitis palmaris and plantaris, parasiticdermatitis, photoallergic contact dermatitis, phototoxic dermatitis,dermatitis pustularis, seborrheic dermatitis, sunburn, toxic dermatitis,Meleney's ulcer, dermatitis veneata, infectious dermatitis, pyogenicdermatitis and rosacea-like dermatitis, and also keratitis, bullosis,vasculitis, cellulitis, panniculitis, lupus erythematosus, erythema,lymphomas, skin cancer, Sweet syndrome, Weber-Christian syndrome, scarformation, wart formation, chilblains), of inflammatory eye diseases(saccoidosis, blepharitis, conjunctivitis, iritis, uveitis,chorioiditis, ophthalmitis), viral diseases (caused by influenza, adenoand corona viruses, for example HPV, HCMV, HIV, SARS), of disorders ofthe skeletal bone and the joints and also the skeletal muscle(multifarious forms of arthritis, for example arthritis alcaptonurica,arthritis ankylosans, arthritis dysenterica, arthritis exsudativa,arthritis fungosa, arthritis gonorrhoica, arthritis mutilans, arthritispsoriatica, arthritis purulenta, arthritis rheumatica, arthritis serosa,arthritis syphilitica, arthritis tuberculosa, arthritis urica, arthritisvillonodularis pigmentosa, atypical arthritis, hemophilic arthritis,juvenile chronic arthritis, rheumatoid arthritis and metastaticarthritis, furthermore Still syndrome, Felty syndrome, Sjdrgen syndrome,Clutton syndrome, Poncet syndrome, Pott syndrome and Reiter syndrome,multifarious forms of arthropathies, for example arthropathia deformans,arthropathia neuropathica, arthropathia ovaripriva, arthropathiapsoriatica and arthropathia tabica, systemic scleroses, multifariousforms of inflammatory myopathies, for example myopathie epidemica,myopathie fibrosa, myopathie myoglobinurica, myopathie ossificans,myopathie ossificans neurotica, myopathie ossificans progressivamultiplex, myopathie purulenta, myopathie rheumatica, myopathietrichinosa, myopathie tropica and myopathie typhosa, and also theGiinther syndrome and the Minchmeyer syndrome), of inflammatory changesof the arteries (multifarious forms of arteritis, for exampleendarteritis, mesarteritis, periarteritis, panarteritis, arteritisrheumatica, arteritis deformans, arteritis temporalis, arteritiscranialis, arteritis gigantocellularis and arteritis granulomatosa, andalso Horton syndrome, Churg-Strauss syndrome and Takayasu arteritis), ofMuckle-Well syndrome, of Kikuchi disease, of polychondritis,dermatosclerosis and also other disorders having an inflammatory orimmunological component, for example cataract, cachexia, osteoporosis,gout, incontinence, lepra, Sezary syndrome and paraneoplastic syndrome,for rejection reactions after organ transplants and for wound healingand angiogenesis in particular in the case of chronic wounds.

Owing to their profile of biochemical and pharmacological properties,the compounds of the invention are particularly suitable for treatmentand/or prevention of interstitial lung diseases, especially idiopathicpulmonary fibrosis (IPF), and also of pulmonary hypertension (PH),bronchiolitis obliterans syndrome (BOS), inflammatory and fibrotic skinand eye disorders and fibrotic disorders of the internal organs.

The aforementioned well-characterized diseases in humans can also occurwith comparable etiology in other mammals and can likewise be treatedtherein with the compounds of the present invention.

In the context of the present invention, the term “treatment” or“treating” includes inhibition, retardation, checking, alleviating,attenuating, restricting, reducing, suppressing, repelling or healing ofa disease, a condition, a disorder, an injury or a health problem, orthe development, the course or the progression of such states and/or thesymptoms of such states. The term “therapy” is understood here to besynonymous with the term “treatment”.

The terms “prevention”, “prophylaxis” and “preclusion” are usedsynonymously in the context of the present invention and refer to theavoidance or reduction of the risk of contracting, experiencing,suffering from or having a disease, a condition, a disorder, an injuryor a health problem, or a development or advancement of such statesand/or the symptoms of such states.

The treatment or prevention of a disease, a condition, a disorder, aninjury or a health problem may be partial or complete.

The present invention thus further provides for the use of the compoundsof the invention for treatment and/or prevention of disorders,especially of the aforementioned disorders.

The present invention further provides for the use of the compounds ofthe invention for production of a medicament for treatment and/orprevention of disorders, especially of the aforementioned disorders.

The present invention further provides a medicament comprising at leastone of the compounds of the invention for treatment and/or prevention ofdisorders, especially of the aforementioned disorders.

The present invention further provides for the use of the compounds ofthe invention in a method for treatment and/or prevention of disorders,especially of the aforementioned disorders.

The present invention further provides a process for treatment and/orprevention of disorders, especially of the aforementioned disorders,using an effective amount of at least one of the compounds of theinvention.

The compounds of the invention can be used alone or, if required, incombination with one or more other pharmacologically active substances,provided that this combination does not lead to undesirable andunacceptable side effects. The present invention therefore furtherprovides medicaments comprising at least one of the compounds of theinvention and one or more further active ingredients, especially fortreatment and/or prevention of the aforementioned disorders.

Preferred examples of combination active ingredients suitable for thispurpose include:

-   -   organic nitrates and NO donors, for example sodium        nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide        dinitrate, molsidomine or SIN-1, and inhaled NO;    -   compounds which inhibit the degradation of cyclic guanosine        monophosphate (cGMP) and/or cyclic adenosine monophosphate        (cAMP), for example inhibitors of phosphodiesterases (PDE) 1, 2,        3, 4 and/or 5, especially PDE 5 inhibitors such as sildenafil,        vardenafil, tadalafil, udenafil, dasantafil, avanafil,        mirodenafil or lodenafil;    -   NO- and heme-independent activators of soluble guanylate cyclase        (sGC), such as in particular the compounds described in WO        01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462        and WO 02/070510;    -   NO-independent but heme-dependent stimulators of soluble        guanylate cyclase (sGC), such as in particular riociguat,        nelociguat and vericiguat, and the compounds described in WO        00/06568, WO 00/06569, WO 02/42301, WO 03/095451, WO        2011/147809, WO 2012/004258, WO 2012/028647 and WO 2012/059549;    -   prostacyclin analogs and IP receptor agonists, by way of example        and with preference iloprost, beraprost, treprostinil,        epoprostenol or selexipag;    -   endothelin receptor antagonists, by way of example and with        preference bosentan, darusentan, ambrisentan or sitaxsentan;    -   compounds which inhibit human neutrophile elastase (HNE), by way        of example and with preference sivelestat or DX-890 (reltran);    -   compounds which inhibit the signal transduction cascade, by way        of example and with preference from the group of the kinase        inhibitors, in particular from the group of the tyrosine kinase        and/or serine/threonine kinase inhibitors, by way of example and        with preference nintedanib, dasatinib, nilotinib, bosutinib,        regorafenib, sorafenib, sunitinib, cediranib, axitinib,        telatinib, imatinib, brivanib, pazopanib, vatalanib, gefitinib,        erlotinib, lapatinib, canertinib, lestaurtinib, pelitinib,        semaxanib or tandutinib;    -   compounds which inhibit the degradation and alteration of the        extracellular matrix, by way of example and with preference        inhibitors of the matrix metalloproteases (MMPs), especially        inhibitors of stromelysin, collagenases, gelatinases and        aggrecanases (in this context particularly of MMP-1, MMP-3,        MMP-8, MMP-9, MMP-10, MMP-11 and MMP-13) and of metalloelastase        (MMP-12);    -   compounds which block the binding of serotonin to its receptors,        by way of example and with preference antagonists of the        5-HT_(2B) receptor such as PRX-08066;    -   antagonists of growth factors, cytokines and chemokines, by way        of example and with preference antagonists of TGF-β, CTGF, IL-1,        IL-4, IL-5, IL-6, IL-8, IL-13 and integrins;    -   Rho kinase-inhibiting compounds, by way of example and with        preference fasudil, Y-27632, SLx-2119, BF-66851, BF-66852,        BF-66853, KI-23095 or BA-1049;    -   compounds which inhibit soluble epoxide hydrolase (sEH), for        example N,N′-dicyclohexylurea,        12-(3-adamantan-1-ylureido)dodecanoic acid or        1-adamantan-1-yl-3-{5-[2-(2-ethoxyethoxy)ethoxy]pentyl}urea;    -   compounds which influence the energy metabolism of the heart, by        way of example and with preference etomoxir, dichloroacetate,        ranolazine or trimetazidine;    -   anti-obstructive agents as used, for example, for treatment of        chronic obstructive pulmonary disease (COPD) or bronchial        asthma, by way of example and with preference from the group of        the inhalatively or systemically administered agonists of the        β-adrenergic receptor (β-mimetics) and the inhalatively        administered anti-muscarinergic substances;    -   antiinflammatory, immunomodulating, immunosuppressive and/or        cytotoxic agents, by way of example and with preference from the        group of the systemically or inhalatively administered        corticosteroids and also acetylcysteine, montelukast,        azathioprine, cyclophosphamide, hydroxycarbamide, azithromycin,        pirfenidone or etanercept;    -   antifibrotic agents, by way of example and with preference        adenosine A2b receptor antagonists, sphingosine-1-phosphate        receptor 3 (S1P3) antagonists, autotaxin inhibitors,        lysophosphatidic acid receptor 1 (LPA-1) and lysophosphatidic        acid receptor 2 (LPA-2) antagonists, lysyl oxidase (LOX)        inhibitors, lysyl oxidase-like 2 inhibitors, CTGF inhibitors,        IL-4 antagonists, IL-13 antagonists, α_(v)β₆-integrin        antagonists, TGF-β antagonists, inhibitors of the Wnt signaling        pathway or CCR2 antagonists;    -   antithrombotic agents, by way of example and with preference        from the group of platelet aggregation inhibitors, the        anticoagulants and the profibrinolytic substances;    -   hypotensive active ingredients, by way of example and with        preference from the group of the calcium antagonists,        angiotensin AII antagonists, ACE inhibitors, vasopeptidase        inhibitors, endothelin antagonists, renin inhibitors, α-receptor        blockers, β-receptor blockers, mineralocorticoid receptor        antagonists and also the diuretics;    -   lipid metabolism modifiers, by way of example and with        preference from the group of the thyroid receptor agonists,        cholesterol synthesis inhibitors, by way of example and with        preference HMG-CoA reductase or squalene synthesis inhibitors,        of the ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR-α,        PPAR-γ and/or PPAR-δ agonists, cholesterol absorption        inhibitors, lipase inhibitors, polymeric bile acid adsorbents,        bile acid reabsorption inhibitors and lipoprotein(a)        antagonists; and/or    -   chemotherapeutics as used, for example, for therapy of neoplasms        in the lung or other organs.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a β-adrenergicreceptor agonist, by way of example and with preference albuterol,isoproterenol, metaproterenol, terbutalin, fenoterol, formoterol,reproterol, salbutamol or salmeterol.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with an antimuscarinergicsubstance, by way of example and with preference ipratropium bromide,tiotropium bromide or oxitropium bromide.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a corticosteroid, by wayof example and with preference prednisone, prednisolone,methylprednisolone, triamcinolone, dexamethasone, beclomethasone,betamethasone, flunisolide, budesonide or fluticasone.

Antithrombotic agents are preferably understood to mean compounds fromthe group of the platelet aggregation inhibitors, the anticoagulants andthe profibrinolytic substances.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a platelet aggregationinhibitor, by way of example and with preference aspirin, clopidogrel,ticlopidine or dipyridamole.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a thrombin inhibitor, byway of example and with preference ximelagatran, melagatran, dabigatran,bivalirudin or clexane.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a GPIIb/IIIa antagonist,by way of example and with preference tirofiban or abciximab.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a factor Xa inhibitor, byway of example and with preference rivaroxaban, apixaban, fidexaban,razaxaban, fondaparinux, idraparinux, DU-176b, PMD-3112, YM-150,KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803,SSR-126512 or SSR-128428.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with heparin or with a lowmolecular weight (LMW) heparin derivative.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a vitamin K antagonist,by way of example and with preference coumarin.

Hypotensive agents are preferably understood to mean compounds from thegroup of the calcium antagonists, angiotensin AII antagonists, ACEinhibitors, endothelin antagonists, renin inhibitors, α-receptorblockers, β-receptor blockers, mineralocorticoid receptor antagonists,and the diuretics.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a calcium antagonist, byway of example and with preference nifedipine, amlodipine, verapamil ordiltiazem.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an al-receptorblocker, by way of example and with preference prazosin.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a β-receptor blocker,by way of example and with preference propranolol, atenolol, timolol,pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol,nadolol, mepindolol, carazalol, sotalol, metoprolol, betaxolol,celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol,adaprolol, landiolol, nebivolol, epanolol or bucindolol.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with an angiotensin AIIantagonist, by way of example and with preference losartan, candesartan,valsartan, telmisartan or embursatan.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with an ACE inhibitor, by wayof example and with preference enalapril, captopril, lisinopril,ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with an endothelin antagonist,by way of example and with preference bosentan, darusentan, ambrisentanor sitaxsentan.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a renin inhibitor, by wayof example and with preference aliskiren, SPP-600 or SPP-800.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a mineralocorticoidreceptor antagonist, by way of example and with preferencespironolactone, eplerenone or finerenone.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a diuretic, by way ofexample and with preference furosemide, bumetanide, torsemide,bendroflumethiazide, chlorothiazide, hydrochlorothiazide,hydroflumethiazide, methyclothiazide, polythiazide, trichlormethiazide,chlorthalidone, indapamide, metolazone, quinethazone, acetazolamide,dichlorphenamide, methazolamide, glycerol, isosorbide, mannitol,amiloride or triamterene.

Lipid metabolism modifiers are preferably understood to mean compoundsfrom the group of the CETP inhibitors, thyroid receptor agonists,cholesterol synthesis inhibitors such as HMG-CoA reductase inhibitors orsqualene synthesis inhibitors, the ACAT inhibitors, MTP inhibitors,PPAR-α, PPAR-γ and/or PPAR-δ agonists, cholesterol absorptioninhibitors, polymeric bile acid adsorbers, bile acid reabsorptioninhibitors, lipase inhibitors and the lipoprotein(a) antagonists.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a CETP inhibitor, by wayof example and with preference torcetrapib (CP-529 414), JJT-705 or CETPvaccine (Avant).

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a thyroid receptoragonist, by way of example and with preference D-thyroxine,3,5,3′-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with an HMG-CoA reductaseinhibitor from the class of statins, by way of example and withpreference lovastatin, simvastatin, pravastatin, fluvastatin,atorvastatin, rosuvastatin or pitavastatin.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a squalene synthesisinhibitor, by way of example and with preference BMS-188494 or TAK-475.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with an ACAT inhibitor, by wayof example and with preference avasimibe, melinamide, pactimibe,eflucimibe or SMP-797.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with an MTP inhibitor, by wayof example and with preference implitapide, BMS-201038, R-103757 orJTT-130.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a PPAR-γ agonist, byway of example and with preference pioglitazone or rosiglitazone.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a PPAR-δ agonist, byway of example and with preference GW 501516 or BAY 68-5042.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a cholesterol absorptioninhibitor, by way of example and with preference ezetimibe, tiqueside orpamaqueside.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a lipase inhibitor, byway of example and with preference orlistat.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a polymeric bile acidadsorber, by way of example and with preference cholestyramine,colestipol, colesolvam, CholestaGel or colestimide.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a bile acid reabsorptioninhibitor, by way of example and with preference ASBT (=IBAT)inhibitors, for example AZD-7806, S-8921, AK-105, BARI-1741, SC-435 orSC-635.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a lipoprotein(a)antagonist, by way of example and with preference gemcabene calcium(CI-1027) or nicotinic acid.

Particular preference is given to combinations of the compounds of theinvention with one or more further active ingredients selected from thegroup consisting of PDE 5 inhibitors, sGC activators, sGC stimulators,prostacyclin analogs, IP receptor agonists, endothelin antagonists,compounds that inhibit the signal transduction cascade and pirfenidone.

The present invention further provides medicaments which comprise atleast one compound of the invention, typically together with one or moreinert, non-toxic, pharmaceutically suitable excipients, and for the usethereof for the aforementioned purposes.

The compounds of the invention can act systemically and/or locally. Forthis purpose, they can be administered in a suitable manner, for exampleby the oral, parenteral, pulmonal, nasal, sublingual, lingual, buccal,rectal, dermal, transdermal, conjunctival or otic route, or as animplant or stent.

The compounds of the invention can be administered in administrationforms suitable for these administration routes.

Suitable administration forms for oral administration are those whichwork according to the prior art and release the compounds of theinvention rapidly and/or in a modified manner and which contain thecompounds of the invention in crystalline and/or amorphized and/ordissolved form, for example tablets (uncoated or coated tablets, forexample with gastric juice-resistant or retarded-dissolution orinsoluble coatings which control the release of the compound of theinvention), tablets or films/oblates which disintegrate rapidly in theoral cavity, films/lyophilizates, capsules (for example hard or softgelatin capsules), sugar-coated tablets, granules, pellets, powders,emulsions, suspensions, aerosols or solutions.

Parenteral administration can bypass an absorption step (e.g. take placeintravenously, intraarterially, intracardially, intraspinally orintralumbally) or include an absorption (e.g. take place inhalatively,intramuscularly, subcutaneously, intracutaneously, percutaneously orintraperitoneally). Administration forms suitable for parenteraladministration include preparations for injection and infusion in theform of solutions, suspensions, emulsions, lyophilizates or sterilepowders.

For the other administration routes, suitable examples are inhalablemedicament forms (including powder inhalers, nebulizers, meteredaerosols), nasal drops, solutions or sprays, tablets, films/oblates orcapsules for lingual, sublingual or buccal administration,suppositories, ear or eye preparations, vaginal capsules, aqueoussuspensions (lotions, shaking mixtures), lipophilic suspensions,ointments, creams, transdermal therapeutic systems (e.g. patches), milk,pastes, foams, sprinkling powders, implants or stents.

Oral and parenteral administration are preferred, especially oral,intravenous and intrapulmonary (inhalative) administration.

The compounds of the invention can be converted to the administrationforms mentioned. This can be accomplished in a manner known per se bymixing with inert, non-toxic, pharmaceutically suitable excipients.These excipients include carriers (for example microcrystallinecellulose, lactose, mannitol), solvents (e.g. liquid polyethyleneglycols), emulsifiers and dispersing or wetting agents (for examplesodium dodecylsulfate, polyoxysorbitan oleate), binders (for examplepolyvinylpyrrolidone), synthetic and natural polymers (for examplealbumin), stabilizers (e.g. antioxidants, for example ascorbic acid),colorants (e.g. inorganic pigments, for example iron oxides) and flavourand/or odour correctants.

In general, it has been found to be advantageous in the case ofparenteral administration to administer amounts of about 0.001 to 1mg/kg, preferably about 0.01 to 0.5 mg/kg, of body weight to achieveeffective results. In the case of oral administration the dosage isabout 0.01 to 100 mg/kg, preferably about 0.01 to 20 mg/kg and mostpreferably 0.1 to 10 mg/kg of body weight. In the case of intrapulmonaryadministration, the amount is generally about 0.1 to 50 mg perinhalation.

It may nevertheless be necessary in some cases to deviate from thestated amounts, specifically as a function of body weight, route ofadministration, individual response to the active ingredient, nature ofthe preparation and time or interval over which administration takesplace. Thus in some cases it may be sufficient to manage with less thanthe abovementioned minimum amount, while in other cases the upper limitmentioned must be exceeded. In the case of administration of greateramounts, it may be advisable to divide them into several individualdoses over the day.

The working examples which follow illustrate the invention. Theinvention is not restricted to the examples.

A. EXAMPLES Abbreviations and Acronyms

-   abs. absolute-   Ac acetyl-   AIBN 2,2′-azobis(2-methylpropionitrile), azobisisobutyronitrile-   aq. aqueous, aqueous solution-   br. broad (in NMR signal)-   Ex. Example-   Bu butyl-   c concentration-   approx. circa, about-   cat. catalytic-   CDI N,N′-carbonyldiimidazole-   CI chemical ionization (in MS)-   d doublet (in NMR)-   d day(s)-   DAST N,N-diethylaminosulfur trifluoride-   TLC thin-layer chromatography-   DCI direct chemical ionization (in MS)-   dd doublet of doublets (in NMR)-   DMF N,N-dimethylformamide-   DMSO dimethyl sulfoxide-   dt doublet of triplets (in NMR)-   ΔT heating, temperature increase (in reaction schemes)-   of th. of theory (in chemical yield)-   EI electron impact ionization (in MS)-   eq. equivalent(s)-   ESI electrospray ionization (in MS)-   Et ethyl-   h hour(s)-   HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HOAc acetic acid-   HPLC high-pressure, high-performance liquid chromatography-   iPr isopropyl-   conc. concentrated (in the case of a solution)-   LC liquid chromatography-   LC/MS liquid chromatography-coupled mass spectrometry-   lit. literature (reference)-   m multiplet (in NMR)-   MCPBA meta-chloroperbenzoic acid, 3-chloroperbenzoic acid-   Me methyl-   min minute(s)-   MS mass spectrometry-   NBS N-bromosuccinimide-   NMR nuclear magnetic resonance spectrometry-   Pd/C palladium on activated carbon-   Pr propyl-   q (or quart) quartet (in NMR)-   qd quartet of doublets (in NMR)-   quant. quantitative (in chemical yield)-   quint quintet (in NMR)-   R_(f) retention index (in TLC)-   RP reverse phase (in HPLC)-   RT room temperature-   R_(t) retention time (in HPLC, LC/MS)-   s singlet (in NMR)-   sept septet (in NMR)-   t triplet (in NMR)-   tBu tert-butyl-   td triplet of doublets (in NMR)-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   UV ultraviolet spectrometry-   v/v volume to volume ratio (of a solution)-   tog. together

HPLC and LC-MS Methods: Method 1 (LC/MS):

Instrument: Waters Acquity SQD UPLC System; column: Waters Acquity UPLCHSS T3 1.8μ 50×1 mm; eluent A: 1 l water+0.25 ml 99% formic acid, eluentB: 1 l acetonitrile+0.25 ml 99% formic acid; gradient: 0.0 min 90% A→1.2min 5% A→2.0 min 5% A; oven: 50° C.; flow rate: 0.40 ml/min; UVdetection: 208-400 nm.

Method 2 (LC/MS):

MS instrument: Waters Micromass QM; HPLC instrument: Agilent 1100series; column: Agilent ZORBAX Extend-C18 3.0 mm×50 mm 3.5μ; eluent A: 1l water+0.01 mol ammonium carbonate, eluent B: 1 l acetonitrile;gradient: 0.0 min 98% A→0.2 min 98% A→3.0 min 5% A→4.5 min 5% A; oven:40° C.; flow rate: 1.75 ml/min; UV detection: 210 nm.

Method 3 (LC/MS):

MS instrument: Agilent MS Quad 6150; HPLC instrument: Agilent 1290;column: Waters Acquity UPLC HSS T3 1.8μ 50×2.1 mm; eluent A: 1 lwater+0.25 ml 99% formic acid, eluent B: 1 l acetonitrile+0.25 ml 99%formic acid; gradient: 0.0 min 90% A→0.3 min 90% A→1.7 min 5% A→3.0 min5% A; oven: 50° C.; flow rate: 1.20 ml/min; UV detection: 205-305 nm.

Method 4 (LC/MS):

MS instrument: Agilent 6130; HPLC instrument: Agilent 1200; UV DAD;column: Waters XBridge BEH XP 2.5 μm, 2.1×50 mm; eluent A: ammoniumacetate (10 mM)+water/methanol/acetonitrile (9.0:0.6:0.4), eluent B:ammonium acetate (10 mM)+water/methanol/acetonitrile (1.0:5.4:3.6);gradient A/B: 80/20 (0.0 min)→80/20 (1.5 min)→0/100 (2.5 min); flowrate: 0.6 ml/min; temperature: 35° C.; UV detection: 215 and 238 nm.

Method 5 (Preparative HPLC):

Column: Reprosil C18, 10 μm, 125×30 mm; eluent: acetonitrile/water with0.1% TFA; gradient: 0-5.00 min 10:90, sample injection at 3.00 min,5.00-23.00 min to 95:5, 23.00-30.00 min 95:5, 30.00-30.50 min to 10:90,30.50-31.20 min 10:90.

Method 6 (Preparative HPLC):

Column: Chromatorex C18, 125×40 mm; eluent A: water+0.05% TFA, eluent B:acetonitrile; gradient: 0.0 min 20% B→4.0 min 20% B→30 min 95% B→35 min95% B→36 min 20% B; flow rate: 50 ml/min.

Method 7 (Preparative HPLC):

Column: Chromatorex C18, 250×30 mm; eluent A: water, eluent B:acetonitrile; gradient: 0.0 min 60% B→4.5 min 80% B→11.5 min 100% B→12min 100% B→14.75 min 60% B; flow rate: 50 ml/min.

Method 8 (Preparative HPLC):

Column: Chromatorex C18, 250×30 mm; eluent A: water, eluent B:acetonitrile; gradient: 0.0 min 40% B→4.5 min 60% B→11.5 min 80% B→12min 100% B→14.75 min 40% B; flow rate: 50 ml/min.

Method 9 (Preparative HPLC):

Column: Chromatorex C18, 250×30 mm; eluent A: water+0.1% TFA, eluent B:acetonitrile; gradient: 0.0 min 40% B→4.5 min 60% B→11.5 min 80% B→12min 100% B→14.75 min 40% B; flow rate: 50 ml/min.

Method 10 (Preparative HPLC):

Column: Reprosil C18, 10 μm, 250×30 mm; flow rate: 50 ml/min; run time:18 min; detection: 210 nm; eluent: water+0.1% formic acid/methanol;gradient: 20% methanol (4.25 min)→40% methanol (4.5 min)→60% methanol(11.5 min)→100% methanol (12 min)→100% methanol (14.5 min)→20% methanol(14.75 min)→20% methanol (18 min).

Method 11 (Preparative HPLC):

Column: GromSil C18, 250×30 mm, 10 μm; flow rate: 50 ml/min; eluent A:water, eluent B: acetonitrile; gradient: 0 min 30% B→4.25 min 30% B→4.5min 50% B→11.5 min 70% B→12 min 100% B→14.5 min 100% B→14.75 min 30%B→18 min 30% B; detection: 210 nm.

Method 12 (Preparative HPLC):

Column: Reprosil C18, 10 μm, 125×30 mm; eluent: acetonitrile/water with0.1% TFA; gradient: 0-5.00 min 10:90, sample injection at 3.00 min,5.00-23.00 min to 95:5, 23.00-30.00 min 95:5, 30.00-30.50 min to 10:90,30.50-31.20 min 10:90.

Method 13 (Preparative HPLC):

Column: Chromatorex C18, 250×30 mm; eluent A: water, eluent B:acetonitrile; gradient: 0.0 min 30% B→4.5 min 50% B→11.5 min 70% B→12min 100% B→14.75 min 30% B; flow rate: 50 ml/min.

Method 14 (Preparative HPLC):

Column: Kinetex 5 μm C18 100 A, 150×21.2 mm; eluent A: water+0.2% formicacid, eluent B: acetonitrile; gradient: 70% A, 30% B, isocratic; flowrate: 25 ml/min.

Method 15 (Preparative HPLC):

Column: Chromatorex C18, 125×30 mm; eluent A: water+0.05% TFA, eluent B:acetonitrile; gradient: 0.0 min 20% B→3.2 min 20% B→18 min 95% B→23 min95% B→24 min 20% B; flow rate: 50 ml/min.

Method 16 (Preparative HPLC):

Column: Reprosil C18, 10 m, 125×30 mm; eluent: acetonitrile/water with0.1% TFA; gradient: 0-6.00 min 5:95, sample injection at 3.00 min;6.00-27.00 min to 35:65; 27.00-30.00 min 95:5, 30.00-33.00 min to 5:95.

Method 17 (Preparative HPLC):

Column: Reprosil C18, 10 μm, 250×30 mm; flow rate: 50 ml/min; run time:18 min; detection: 210 nm; eluent: water+0.1% formic acid/methanol;gradient: 20% methanol (4.25 min)→40% methanol (4.5 min)→60% methanol(11.5 min)→100% methanol (12 min)→100% methanol (14.5 min)→20% methanol(14.75 min)→20% methanol (18 min).

Method 18 (Preparative HPLC):

Column: Reprosil C18, 10 μm, 125×30 mm; eluent: acetonitrile/water with0.1% TFA; flow rate: 75 ml/min; gradient: 0-5.50 min 10:90, sampleinjection at 3.00 min, 5.50-17.65 min to 95:5, 17.65-19.48 min 95:5,19.48-19.66 min to 10:90, 19.66-20.72 min 10:90.

Method 19 (Preparative HPLC):

Column: Reprosil C18, 10 m, 125×30 mm; eluent: acetonitrile/water with0.1% TFA; gradient: 0-6.00 min 35:65, sample injection at 3.00 min;6.00-27.00 min to 80:20; 27.00-30.00 min 95:5, 30.00-33.00 min to 35:65.

Method 20 (Preparative HPLC):

Column: Reprosil C18, 10 μm, 125×30 mm; eluent: acetonitrile/water with0.1% TFA; gradient: 0-6.00 min 35:65, sample injection at 3.00 min;6.00-27.00 min to 80:20; 27.00-51.00 min 95:5, 51.00-53.00 min to 35:65.

Method 21 (LC/MS):

Instrument: Agilent MS Quad 6150 with HPLC Agilent 1290; column: WatersAcquity UPLC HSS T3 1.8 μm 50 mm×2.1 mm; eluent A: 1 l water+0.25 ml 99%formic acid, eluent B: 1 l acetonitrile+0.25 ml 99% formic acid;gradient: 0.0 min 90% A→0.3 min 90% A→1.7 min 5% A→3.0 min 5% A; flowrate: 1.20 ml/min; temperature: 50° C.; UV detection: 205-305 nm.

Method 22 (LC/MS):

Instrument: Micromass Quattro Premier with Waters UPLC Acquity; column:Thermo Hypersil GOLD 1.9μ 50×1 mm; eluent A: 1 l water+0.5 ml 50% formicacid, eluent B: 1 l acetonitrile+0.5 ml 50% formic acid; gradient: 0.0min 97% A→0.5 min 97% A→3.2 min 5% A→4.0 min 5% A; oven: 50° C.; flowrate: 0.30 ml/min; UV detection: 210 nm.

Method 23 (LC/MS):

Instrument: Waters Acquity SQD UPLC System; column: Waters Acquity UPLCHSS T3 1.8μ 50×1 mm; eluent A: 1 l water+0.25 ml 99% formic acid, eluentB: 1 l acetonitrile+0.25 ml 99% formic acid; gradient: 0.0 min 95% A→6.0min 5% A→7.5 min 5% A; oven: 50° C.; flow rate: 0.35 ml/min; UVdetection: 210-400 nm.

Method 24 (Preparative HPLC):

Column: Reprosil C18, 10 μm, 250×40 mm; eluent: acetonitrile/water with0.1% TFA; gradient: 0-6.00 min 10:90, sample injection at 3.00 min,6.00-27.00 min to 95:5, 27.00-38.00 min 95:5, 38.00-39.00 min to 10:90,39.00-40.20 min 10:90.

Further Details:

The percentages in the example and test descriptions which follow are,unless indicated otherwise, percentages by weight; parts are parts byweight. Solvent ratios, dilution ratios and concentration data forliquid/liquid solutions are based in each case on volume.

Purity figures are generally based on corresponding peak integrations inthe LC/MS chromatogram, but may additionally also have been determinedwith the aid of the ¹H NMR spectrum. If no purity is indicated, thepurity is generally 100% according to automated peak integration in theLC/MS chromatogram, or the purity has not been determined explicitly.

Stated yields in % of theory are generally corrected for purity if apurity of <100% is indicated. In solvent-containing or contaminatedbatches, the formal yield may be “>100%”; in these cases the yield isnot corrected for solvent or purity.

The descriptions of the coupling patterns of ¹H NMR signals that followhave in some cases been taken directly from the suggestions of the ACDSpecManager (ACD/Labs Release 12.00, Product version 12.5) and have notnecessarily been strictly scrutinized. In some cases, the suggestions ofthe SpecManager were adjusted manually. Manually adjusted or assigneddescriptions are generally based on the optical appearance of thesignals in question and do not necessarily correspond to a strict,physically correct interpretation. In general, the stated chemical shiftrefers to the center of the signal in question. In the case of broadmultiplets, an interval is given. Signals obscured by solvent or waterwere either tentatively assigned or have not been listed. Significantlybroadened signals—caused, for example, by rapid rotation of molecularmoieties or because of exchanging protons—were likewise assignedtentatively (often referred to as a broad multiplet or broad singlet) orare not listed.

Melting points and melting-point ranges, if stated, are uncorrected.

All reactants or reagents whose preparation is not described explicitlyhereinafter were purchased commercially from generally accessiblesources. For all other reactants or reagents whose preparation likewiseis not described hereinafter and which were not commercially obtainableor were obtained from sources which are not generally accessible, areference is given to the published literature in which theirpreparation is described.

In the case of the synthesis intermediates and working examples of theinvention described hereinafter, any compound specified in the form of asalt of the corresponding base or acid is generally a salt of unknownexact stoichiometric composition, as obtained by the respectivepreparation and/or purification process. Unless specified in moredetail, additions to names and structural formulae, for example“hydrochloride”, “formate”, “acetate”, “trifluoroacetate”, “sodium salt”or “x HCl”, “x HCOOH”, “x CH₃COOH”, “x CF₃COOH”, “x Na⁺” shouldtherefore not be understood in a stoichiometric sense in the case ofsuch salts, but are merely of descriptive character with regard to thesalt-forming components present.

Starting Compounds and Intermediates Example 1A6-Bromo-3-methyl-2-phenylquinoline-4-carboxylic Acid

To 100.0 g (398.16 mmol, 90% purity) of 5-bromo-1H-indole-2,3-dione and59.4 g (442.41 mmol) of 1-phenylpropan-1-one were added 1.2 liters ofacetic acid, and the mixture was stirred at 75° C. for 20 min.Thereafter, 400 ml of conc. hydrochloric acid were added to the reactionmixture, and stirring of the mixture was continued at 105° C. overnight.The reaction solution was then added to a mixture of 10 liters of 1 Nhydrochloric acid, 9.2 liters of water and 840 ml of conc. hydrochloricacid while stirring. 1 liter of ice-water was added to the mixture, andthe precipitate was filtered off with the aid of a frit. The filterresidue was washed twice with 500 ml of water, then extracted bystirring twice with 150 ml each time of a 3:1 mixture of tert-butylmethyl ether and acetone and filtered again. The residue was extractedby stirring three times more with 100 ml each time of tert-butyl methylether and finally dried under reduced pressure. 117.96 g (78% of theory,100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=14.39 (br. s, 1H), 8.01 (d, 1H),7.94-7.90 (m, 2H), 7.63-7.61 (m, 2H), 7.56-7.49 (m, 3H), 2.40 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=0.76 min, m/z=343 [M+H]⁺.

Example 2A(6-Bromo-3-methyl-2-phenylquinolin-4-yl)(1H-imidazol-1-yl)methanone

100.0 g (292.23 mmol) of the compound from example 1A were suspended in1.5 liters of DMF, and 95.0 g (584.45 mmol) of N,N′-carbonyldiimidazolewere added at RT. The reaction mixture was stirred first at 60° C. for 4h and then at RT overnight. While cooling with an ice bath, 1.5 litersof ice-water were added gradually and then the mixture was put in thefridge for three days. The precipitated solids were filtered off bymeans of a frit, washed three times with 250 ml of water and dried underreduced pressure. 103.41 g (85% of theory, 94% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=8.6-8.0 (br. m, 1H), 8.09 (d, 1H),8.0-7.5 (br. m, 1H), 7.97 (dd, 1H), 7.82 (s, 1H), 7.72-7.66 (m, 2H),7.59-7.48 (m, 3H), 7.22 (br. s, 1H), 2.25 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.16 min, m/z=392/394 [M+H]⁺.

Example 3A 6-Fluoro-3-methyl-2-phenylquinoline-4-carboxylic Acid

1.00 g (6.06 mmol) of 5-fluoro-1H-indole-2,3-dione were initiallycharged in 16.5 ml of acetic acid, and 813 mg (6.06 mmol) of1-phenylpropan-1-one were added. The reaction mixture was stirred at 75°C. for 5 min. Subsequently, 5.5 ml of conc. hydrochloric acid wereadded, and stirring of the mixture was continued at 105° C. for 3 h.After cooling to RT, the reaction mixture was added to 200 ml of 1 Mhydrochloric acid and the precipitated solids were filtered off withsuction. The solids were washed with water and dried under reducedpressure. 670 mg (35% purity, 14% of theory) of the title compound wereobtained.

LC/MS (Method 1, ESIpos): R_(t)=0.64 min, m/z=282 [M+H]⁺.

Example 4A(6-Fluoro-3-methyl-2-phenylquinolin-4-yl)(1H-imidazol-1-yl)methanone

To a solution of 1.50 g (5.33 mmol) of the compound from example 3A in23 ml of DMF were added, at RT, 951 mg (5.87 mmol) ofN,N′-carbonyldiimidazole, and the mixture was stirred at 60° C. for 3 h.Subsequently, a further 300 mg (1.07 mmol) of N,N′-carbonyldiimidazolewere added, and the mixture was stirred at 60° C. for a further 15 h.After cooling to RT, the mixture was introduced into 100 ml of waterwhile stirring and a little ice was added. The solids formed werefiltered off and dried under reduced pressure. 1.57 g (89% of theory,100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=8.5-8.0 (br. m, 1H), 8.22 (dd, 1H),8.0-7.5 (br. m, 1H), 7.76 (td, 1H), 7.69 (dd, 2H), 7.59-7.47 (m, 3H),7.41 (dd, 1H), 7.21 (br. s, 1H), 2.25 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.05 min, m/z=332 [M+H]⁺.

Example 5A 6-Iodo-3-methyl-2-phenylquinoline-4-carboxylic acid

20.0 g (73.25 mmol) of 5-iodo-1H-indole-2,3-dione were initially chargedin 200 ml of acetic acid, and 9.83 g (73.25 mmol) of1-phenylpropan-1-one were added. The reaction mixture was stirred at 75°C. for 5 min. Thereafter, 66 ml of conc. hydrochloric acid were added,and stirring of the mixture was continued at 105° C. overnight.Subsequently, the reaction solution was introduced cautiously into waterwhile stirring. The precipitate formed was filtered off and washed twicewith water and twice with a little tert-butyl methyl ether. After dryingunder reduced pressure overnight, 11.10 g (32% of theory, 82% purity) ofthe title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=14.36 (br. s, 1H), 8.13 (d, 1H), 8.05(dd, 1H), 7.84 (d, 1H), 7.66-7.57 (m, 2H), 7.57-7.41 (m, 3H), 2.39 (s,3H).

LC/MS (Method 1, ESIpos): R_(t)=0.78 min, m/z=390 [M+H]⁺.

Example 6A(1H-Imidazol-1-yl)(6-iodo-3-methyl-2-phenylquinolin-4-yl)methanone

600 mg (1.23 mmol, 80% purity) of the compound from example 5A weredissolved in 5.5 ml of DMF, and 400 mg (2.47 mmol) ofN,N′-carbonyldiimidazole were added at RT. The reaction mixture wasstirred at 60° C. overnight and then, after cooling to RT, water andethyl acetate were added. The phases were separated and the aqueousphase was extracted three times with ethyl acetate. The combined organicphases were dried over sodium sulfate, filtered and concentrated. Theresidue was purified by means of column chromatography (80 g of silicagel, eluent: cyclohexane/ethyl acetate 5:1, Biotage). After the solventhad been removed under reduced pressure, the residue was dried underreduced pressure overnight. 568 mg (98% of theory, 94% purity) of thetitle compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=9.50-6.00 (br. m, 2H), 8.10 (dd, 1H),7.95 (s, 1H), 7.91 (d, 1H), 7.72-7.65 (m, 2H), 7.60-7.42 (m, 3H), 7.22(br. s, 1H), 2.24 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.13 min, m/z=440 [M+H]⁺.

Example 7A 3,6-Dimethyl-2-phenylquinoline-4-carboxylic Acid

2.00 g (12.41 mmol) of 5-methyl-1H-indole-2,3-dione were initiallycharged in 33.7 ml of acetic acid, and 1.66 g (12.41 mmol) of1-phenylpropan-1-one were added. The reaction mixture was stirred at 75°C. for 5 min. Subsequently, 11.3 ml of conc. hydrochloric acid wereadded, and stirring of the mixture was continued at 105° C. overnight.After cooling to RT, the reaction mixture was added to 400 ml of 1 Mhydrochloric acid and this mixture was then left to stand at RT forthree days. The precipitated solids were filtered off, washed with waterand dried under reduced pressure. 700 mg (20% of theory, 100% purity) ofthe title compound were obtained.

LC/MS (Method 1, ESIpos): R_(t)=0.53 min, m/z=278 [M+H]⁺.

Example 8A(3,6-Dimethyl-2-phenylquinolin-4-yl)(1H-imidazol-1-yl)methanone

To a solution of 464 mg (1.68 mmol) of the compound from example 7A in 7ml of DMF were added, at RT, 299 mg (1.84 mmol) ofN,N′-carbonyldiimidazole, and the mixture was stirred at 60° C. for 4 h.Subsequently, a further 30 mg (0.18 mmol) of N,N′-carbonyldiimidazolewere added, and the mixture was stirred at 60° C. for a further hour.After cooling to RT, water was added and the mixture was extracted threetimes with ethyl acetate. The combined organic phases were washed oncewith saturated sodium chloride solution, dried over sodium sulfate,filtered and concentrated. The residue was taken up in dichloromethane,concentrated again and dried under reduced pressure. 505 mg (92% oftheory, 100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=8.5-8.0 (br. m, 1H), 8.04 (d, 1H),8.0-7.5 (br. m, 1H), 7.98-7.59 (m, 3H), 7.57-7.45 (m, 3H), 7.34 (s, 1H),7.26-7.09 (m, 1H), 2.46 (s, 3H), 2.23 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.05 min, m/z=328 [M+H]⁺.

Example 9A 6-Ethyl-3-methyl-2-phenylquinoline-4-carboxylic acid

1.00 g (5.71 mmol) of 5-ethyl-1H-indole-2,3-dione were initially chargedin 15.5 ml of acetic acid, and 766 mg (5.71 mmol) of1-phenylpropan-1-one were added. The reaction mixture was stirred at 75°C. for 5 min. Subsequently, 5.2 ml of conc. hydrochloric acid wereadded, and stirring of the mixture was continued at 105° C. overnight.After cooling to RT, the reaction mixture was added to 200 ml of 1 Mhydrochloric acid and the precipitated solids were filtered off. Thesolids were washed with water and dried under reduced pressure. 780 mg(46% of theory, 99% purity) of the title compound were obtained.

LC/MS (Method 1, ESIpos): R_(t)=0.63 min, m/z=292 [M+H]⁺.

Example 10A(6-Ethyl-3-methyl-2-phenylquinolin-4-yl)(1H-imidazol-1-yl)methanone

To a solution of 640 mg (2.20 mmol) of the compound from example 9A in10 ml of DMF were added, at RT, 392 mg (2.42 mmol) ofN,N′-carbonyldiimidazole, and the mixture was stirred at 60° C. for 3.5h. Subsequently, the mixture was cooled to RT, water was added and themixture was extracted three times with ethyl acetate. The combinedorganic phases were washed once with saturated sodium chloride solution,dried over sodium sulfate, filtered and concentrated, and the residuewas dried under reduced pressure. The residue was purified by means ofcolumn chromatography (50 g of silica gel, eluent: cyclohexane/ethylacetate 7:3, Biotage). 362 mg (46% of theory, 95% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=8.5-8.0 (br. m, 1H), 8.07 (d, 1H),8.0-7.5 (br. m, 1H), 7.73 (dd, 1H), 7.70-7.65 (m, 2H), 7.57-7.47 (m,3H), 7.32 (br. s, 1H), 7.22 (br. s, 1H), 2.76 (q, 2H), 2.24 (s, 3H),1.19 (t, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.18 min, m/z=342 [M+H]⁺.

Example 11A 6-Isopropyl-3-methyl-2-phenylquinoline-4-carboxylic acid

2.50 g (13.21 mmol) of 5-isopropyl-1H-indole-2,3-dione were initiallycharged together with 36 ml of acetic acid and 1.77 g (13.21 mmol) of1-phenylpropan-1-one, and the reaction mixture was stirred at 75° C. for5 min. Then 12 ml of conc. hydrochloric acid were added, and stirring ofthe mixture was continued at 105° C. overnight. After cooling to RT, thereaction mixture was added to 500 ml of 1 M hydrochloric acid and theprecipitated solids were filtered off. The solids were washed with waterand dried under reduced pressure. 2.04 g (31% of theory, 62% purity) ofthe title compound were obtained.

LC/MS (Method 1, ESIpos): R_(t)=0.66 min, m/z=306 [M+H]⁺.

Example 12A 3-Methyl-2-phenyl-6-(trifluoromethyl)quinoline-4-carboxylicAcid

1.00 g (4.65 mmol) of 5-(trifluoromethyl)-1H-indole-2,3-dione wereinitially charged together with 12.6 ml of acetic acid and 624 mg (4.65mmol) of 1-phenylpropan-1-one, and the reaction mixture was stirred at75° C. for 5 min. Then 4.2 ml of conc. hydrochloric acid were added, andstirring of the mixture was continued at 105° C. overnight. Aftercooling to RT, the reaction mixture was added to 200 ml of 1 Mhydrochloric acid and the precipitated solids were filtered off. Thesolids were washed with water and dried under reduced pressure. 1.17 g(75% of theory, 100% purity) of the title compound were obtained.

LC/MS (Method 1, ESIpos): R_(t)=0.91 min, m/z=332 [M+H]⁺.

Example 13A 3-Methyl-2-phenyl-6-(trifluoromethoxy)quinoline-4-carboxylicAcid

To a mixture of 2.5 g (10.82 mmol) of5-(trifluoromethoxy)-1H-indole-2,3-dione in 25 ml of acetic acid wereadded 1.45 g (10.82 mmol) of 1-phenylpropan-1-one. After stirring at 75°C. for 5 min, 8 ml of conc. hydrochloric acid were added, and stirringof the mixture was continued at 110° C. for 5 h. After cooling to RT andleaving to stand overnight, the mixture was introduced into 500 ml of 1M hydrochloric acid while stirring. After a few minutes, the solidsformed were filtered off, washed twice with water and dried underreduced pressure. 3.16 g (77% of theory, 92% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=14.41 (br. s, 1H), 8.21 (d, 1H), 7.80(dd, 1H), 7.69 (d, 1H), 7.66-7.58 (m, 2H), 7.57-7.47 (m, 3H), 2.41 (s,3H).

LC/MS (Method 1, ESIpos): R_(t)=0.97 min, m/z=348 [M+H]⁺.

Example 14A (1H-Imidazol-1-yl)[3-methyl-2-phenyl-6-(trifluoromethoxy)quinolin-4-yl]methanone

To a solution of 1.50 g (3.97 mmol, 92% purity) of the compound fromexample 13A in 15 ml of DMF were added, at RT, 709 mg (4.37 mmol) ofN,N′-carbonyldiimidazole, and the mixture was stirred at 60° C. for 3 h.Subsequently, a further 709 mg (4.37 mmol) of N,N′-carbonyldiimidazolewere added, and the mixture was stirred at 60° C. for a further 4 h.After being left to stand at RT overnight, the mixture was first stirredat 80° C. for a further hour. Thereafter, another 709 mg (4.37 mmol) ofN,N′-carbonyldiimidazole were added, and the mixture was stirred at 100°C. for another 4 h. After being left to stand at RT overnight, themixture was introduced into ice-water while stirring and adjusted to pH4 by means of 10% aqueous citric acid solution. Subsequently, themixture was extracted twice with ethyl acetate. The combined organicphases were washed once with saturated sodium chloride solution, driedover sodium sulfate, filtered and concentrated. The residue wasprepurified by means of column chromatography (100 g of silica gel,eluent: cyclohexane/ethyl acetate 7:3, Biotage). The product thusobtained was stirred in pentane, and the solids present were filteredoff and dried under reduced pressure. 1.28 g (81% of theory, 100%purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=8.5-8.0 (br. m, 1H), 8.30 (d, 1H),8.0-7.5 (br. m, 1H), 7.84 (dd, 1H), 7.72-7.66 (m, 2H), 7.59-7.50 (m,4H), 7.21 (br. s, 1H), 2.26 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.15 min, m/z=398 [M+H]⁺.

Example 15A 6-Bromo-3-ethyl-2-phenylquinoline-4-carboxylic Acid

1.00 g (4.42 mmol) of 5-bromo-1H-indole-2,3-dione were initially chargedin 12.0 ml of acetic acid, and 656 mg (4.42 mmol) of 1-phenylbutan-1-onewere added. The reaction mixture was stirred at 75° C. for 5 min.Subsequently, 4.0 ml of conc. hydrochloric acid were added, and stirringof the mixture was continued at 105° C. overnight. After cooling to RT,the reaction mixture was added to 200 ml of 1 M hydrochloric acid andthe precipitated solids were filtered off with suction. The solids werewashed with water and dried under reduced pressure. 1.20 g (55% oftheory, 72% purity) of the title compound were obtained.

LC/MS (Method 1, ESIpos): R_(t)=0.88 min, m/z=357 [M+H]⁺.

Example 16A(6-Bromo-3-ethyl-2-phenylquinolin-4-yl)(1H-imidazol-1-yl)methanone

To a solution of 500 mg (1.40 mmol) of the compound from example 15A in6 ml of DMF were added, at RT, 250 mg (1.54 mmol) ofN,N′-carbonyldiimidazole, and the mixture was stirred at bathtemperature 60° C. for 5 h. Subsequently added to the mixture were 100ml each of water and ethyl acetate. After phase separation, the aqueousphase was extracted once with ethyl acetate. The combined organic phaseswere washed once with saturated sodium chloride solution, dried oversodium sulfate, filtered and concentrated. The residue was taken up indichloromethane and purified by means of column chromatography (50 g ofsilica gel, eluent: cyclohexane/ethyl acetate 7:3, Biotage). 259 mg (45%of theory, 100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.5-7.5 (br. m, 2H), 8.08 (d, 1H),7.97 (dd, 1H), 7.77 (br. s, 1H), 7.69-7.60 (m, 2H), 7.59-7.47 (m, 3H),7.22 (br. s, 1H), 2.82-2.69 (m, 1H), 2.53-2.44 (m, 1H, partiallyhidden), 0.81 (t, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.16 min, m/z=406/408 [M+H]⁺.

Example 17A 6-Bromo-2-phenyl-3-propylquinoline-4-carboxylic Acid

300 mg (1.33 mmol) of 5-bromo-1H-indole-2,3-dione were initially chargedin 3.6 ml of acetic acid, and 237 mg (1.46 mmol) of 1-phenylpentan-1-onewere added. The reaction mixture was stirred at 75° C. for 5 min.Subsequently, 1.2 ml of conc. hydrochloric acid were added, and stirringof the mixture was continued at 105° C. overnight. After cooling to RT,the reaction mixture was added to 200 ml of 1 M hydrochloric acid andthe precipitated solids were filtered off with suction. The solids werewashed with water and dried under reduced pressure. 246 mg (35% oftheory, 70% purity) of the title compound were obtained.

LC/MS (Method 1, ESIpos): R_(t)=0.97 min, m/z=371 [M+H]⁺.

Example 18A(6-Bromo-2-phenyl-3-propylquinolin-4-yl)(1H-imidazol-1-yl)methanone

To a solution of 500 mg (1.35 mmol) of the compound from example 17A in6 ml of DMF were added, at RT, 241 mg (1.49 mmol) ofN,N′-carbonyldiimidazole, and the mixture was stirred at bathtemperature 60° C. for 5 h. Subsequently added to the mixture were 100ml each of water and ethyl acetate. After phase separation, the aqueousphase was extracted once with ethyl acetate. The combined organic phaseswere washed once with saturated sodium chloride solution, dried oversodium sulfate, filtered and concentrated. The residue was taken up indichloromethane and purified by means of column chromatography (50 g ofsilica gel, eluent: cyclohexane/ethyl acetate 7:3, Biotage). 355 mg (62%of theory, 100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=8.5-7.5 (br. m, 2H), 8.08 (d, 1H), 7.97(dd, 1H), 7.77 (br. s, 1H), 7.68-7.62 (m, 2H), 7.58-7.48 (m, 3H), 7.22(br. s, 1H), 2.81-2.70 (m, 1H), 2.47-2.36 (m, 1H), 1.30-1.08 (m, 2H),0.55 (t, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.25 min, m/z=420/422 [M+H]⁺.

Example 19A 6-Bromo-7-chloro-3-methyl-2-phenylquinoline-4-carboxylicacid

To a mixture of 521 mg (2.00 mmol) of5-bromo-6-chloro-1H-indole-2,3-dione in 4.5 ml of acetic acid were added268 mg (2.00 mmol) of propiophenone. After stirring at 75° C. for 5 min,1.5 ml of conc. hydrochloric acid were added, and stirring of themixture was continued at 110° C. for 6 h. After cooling down to RT andbeing left to stand overnight, the mixture was stirred at 110° C. for afurther 6 h. Thereafter, the mixture was introduced into 100 ml of 1 Nhydrochloric acid while stirring. After a few minutes, the solids formedwere filtered off, washed twice with water and dried under reducedpressure. 612 mg (58% of theory, 71% purity) of the title compound wereobtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=14.45 (br. s, 1H), 8.35 (s, 1H), 8.15(s, 1H), 7.64-7.58 (m, 2H), 7.57-7.48 (m, 3H), 2.40 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.08 min, m/z=376/378 [M+H]⁺.

Example 20A(6-Bromo-7-chloro-3-methyl-2-phenylquinolin-4-yl)(1H-imidazol-1-yl)methanone

To a solution of 608 mg (1.15 mmol, 71% purity) of the compound fromexample 19A in 3 ml of DMF were added, at RT, 204 mg (1.26 mmol) ofN,N′-carbonyldiimidazole, and the mixture was stirred at 60° C. for 8 h.Then 100 ml each of water and ethyl acetate were added to the mixture.After phase separation, the aqueous phase was extracted once with ethylacetate. The combined organic phases were washed once with saturatedsodium chloride solution, dried over sodium sulfate, filtered andconcentrated. The residue was taken up in dichloromethane and purifiedby means of column chromatography (50 g of silica gel, eluent:cyclohexane/ethyl acetate 7:3, Biotage). 446 mg (86% of theory, 94%purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=8.5-7.7 (br. m, 2H), 8.44 (s, 1H), 8.09(s, 1H), 7.72-7.65 (m, 2H), 7.60-7.50 (m, 3H), 7.21 (br. s, 1H), 2.24(s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.21 min, m/z=426/428 [M+H]⁺.

Example 21A 6,7-Dichloro-3-methyl-2-phenylquinoline-4-carboxylic acid

10.0 g (46.29 mmol) of a regioisomer mixture of4,5-dichloro-1H-indole-2,3-dione and 5,6-dichloro-1H-indole-2,3-dione[about 1:1, preparation described in J. Med. Chem. 2004, 47 (4),935-946] were initially charged in 136 ml of acetic acid, and 6.21 g(46.29 mmol) of 1-phenylpropan-1-one were added. The reaction mixturewas stirred at 75° C. for 5 min. Then 42 ml of conc. hydrochloric acidwere added, and stirring of the mixture was continued at 105° C.overnight. Subsequently, the reaction solution was introduced cautiouslyinto water while stirring. The precipitate formed was filtered off andprepurified by means of column chromatography (silica gel, eluent: ethylacetate/methanol 10:1). The product mixture thus obtained was dissolvedin 120 ml of acetonitrile/methanol/water/trifluoroacetic acid mixturewhile heating and separated into the regioisomers by means ofpreparative HPLC [column: Kinetix C18, 5 μm, 100×21.2 mm; flow rate: 25ml/min; detection: 210 nm; injection volume: 1.0 ml; temperature: 35°C.; eluent: 45% water/50% acetonitrile/5% formic acid (1% in water),isocratic; run time: 4.3 min]. 380 mg (2.2% of theory, 90% purity) ofthe title compound and 300 mg (1.9% of theory, 100% purity) of theregioisomeric compound from example 23A were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=14.54 (br. s, 1H), 8.37 (s, 1H), 8.00(s, 1H), 7.68-7.58 (m, 2H), 7.58-7.47 (m, 3H), 2.40 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=0.99 min, m/z=332 [M+H]⁺.

Example 22A(6,7-Dichloro-3-methyl-2-phenylquinolin-4-yl)(1H-imidazol-1-yl)methanone

To a solution of 328 mg (0.99 mmol) of the compound from example 21A in4.4 ml of DMF were added, at RT, 320 mg (1.98 mmol) ofN,N′-carbonyldiimidazole, and the mixture was stirred at 60° C.overnight. Then water and ethyl acetate were added to the mixture. Afterphase separation, the aqueous phase was extracted three times with ethylacetate. The combined organic phases were washed once with saturatedsodium chloride solution, dried over sodium sulfate, filtered andconcentrated. The residue was purified by means of column chromatography(80 g of silica gel, eluent: cyclohexane/ethyl acetate 2:1, Biotage). Inthis way, 295 mg (70% of theory, 90% purity) of the title compound wereobtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=9.25-6.25 (br. m, 2H), 8.46 (s, 1H),7.97 (s, 1H), 7.75-7.63 (m, 2H), 7.63-7.38 (m, 3H), 7.21 (br. s, 1H),2.24 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.19 min, m/z=382 [M+H]⁺.

Example 23A 5,6-Dichloro-3-methyl-2-phenylquinoline-4-carboxylic Acid

As described under example 21A, 10.0 g (46.29 mmol) of a regioisomermixture of 4,5-dichloro-1H-indole-2,3-dione and5,6-dichloro-1H-indole-2,3-dione (about 1:1) were used to obtain 300 mg(1.9% of theory, 100% purity) of the title compound.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=7.92 (d, 1H), 7.82 (d, 1H), 7.58-7.43(m, 5H), 2.29 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=0.95 min, m/z=332 [M+H]⁺.

Example 24A(5,6-Dichloro-3-methyl-2-phenylquinolin-4-yl)(1H-imidazol-1-yl)methanone

To a solution of 274 mg (0.83 mmol) of the compound from example 23A in3.7 ml of DMF were added, at RT, 268 mg (1.65 mmol) ofN,N′-carbonyldiimidazole, and the mixture was stirred at 60° C.overnight. Then the mixture was stirred in a microwave apparatus at 150°C. for 3 h. After a further 268 mg (1.65 mmol) ofN,N′-carbonyldiimidazole had been added, the mixture was stirred in themicrowave at 150° C. for another 1 h. After cooling down to RT, waterand ethyl acetate were added to the mixture, the phases were separatedand then the aqueous phase was extracted three times with ethyl acetate.The combined organic phases were washed once with saturated sodiumchloride solution, dried over sodium sulfate, filtered and concentrated.The residue was purified by means of column chromatography (80 g ofsilica gel, eluent: cyclohexane/ethyl acetate 2:1→ethyl acetate/methanol10:1, Biotage). 108 mg (32% of theory, 94% purity) of the title compoundwere obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=9.0-7.0 (br. m, 2H), 8.19 (d, 1H), 8.07(d, 1H), 7.72-7.65 (m, 2H), 7.59-7.50 (m, 3H), 7.28 (br. s, 1H), 2.25(s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.17 min, m/z=382 [M+H]⁺.

Example 25A 6-Bromo-2-(4-fluorophenyl)-3-methylquinoline-4-carboxylicacid

1.00 g (4.42 mmol) of 5-bromo-1H-indole-2,3-dione were initially chargedin 12.0 ml of acetic acid, and 673 mg (4.42 mmol) of1-(4-fluorophenyl)propan-1-one were added. The reaction mixture wasstirred at 75° C. for 5 min. Subsequently, 4.0 ml of conc. hydrochloricacid were added, and stirring of the mixture was continued at 105° C.overnight. After cooling to RT, the reaction mixture was added to 200 mlof 1 M hydrochloric acid and the precipitated solids were filtered off.The solids were washed with water and dried under reduced pressure. 1.29g (73% of theory, 90% purity) of the title compound were obtained.

LC/MS (Method 1, ESIpos): R_(t)=0.88 min, m/z=360 [M+H]⁺.

Example 26A[6-Bromo-2-(4-fluorophenyl)-3-methylquinolin-4-yl](1H-imidazol-1-yl)methanone

To a solution of 500 mg (1.39 mmol) of the compound from example 25A in6 ml of DMF were added, at RT, 248 mg (1.53 mmol) ofN,N′-carbonyldiimidazole, and the mixture was stirred first at bathtemperature 60° C. for 5 h and then at RT for 14 h. Subsequently, afurther 124 mg (0.76 mmol) of N,N′-carbonyldiimidazole were added, andthe mixture was stirred at bath temperature 60° C. for another 7 h.Thereafter, 100 ml each of water and ethyl acetate were added to themixture, the phases were separated and then the aqueous phase wasextracted once with ethyl acetate. The combined organic phases werewashed once with saturated sodium chloride solution, dried over sodiumsulfate, filtered and concentrated. The residue was taken up indichloromethane and purified by means of column chromatography (50 g ofsilica gel, eluent: cyclohexane/ethyl acetate 7:3, Biotage). 402 mg (71%of theory, 100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=8.5-7.5 (br. m, 2H), 8.09 (d, 1H), 7.97(dd, 1H), 7.82 (br. s, 1H), 7.79-7.72 (m, 2H), 7.37 (t, 2H), 7.21 (br.s, 1H), 2.25 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.13 min, m/z=410/412 [M+H]⁺.

Example 27A 6-Bromo-2-(3-fluorophenyl)-3-methylquinoline-4-carboxylicAcid

1.00 g (4.42 mmol) of 5-bromo-1H-indole-2,3-dione were initially chargedin 12.0 ml of acetic acid, and 673 mg (4.42 mmol) of1-(3-fluorophenyl)propan-1-one were added. The reaction mixture wasstirred at 75° C. for 5 min. Subsequently, 4.0 ml of conc. hydrochloricacid were added, and stirring of the mixture was continued at 105° C.overnight. After cooling to RT, the reaction mixture was added to 200 mlof 1 M hydrochloric acid and the precipitated solids were filtered off.The solids were washed with water and dried under reduced pressure. 1.20g (63% of theory, 83% purity) of the title compound were obtained.

LC/MS (Method 1, ESIpos): R_(t)=0.94 min, m/z=360 [M+H]⁺.

Example 28A [6-Bromo-2-(3-fluorophenyl)-3-methylquinolin-4-yl](1H-imidazol-1-yl)methanone

To a solution of 500 mg (1.39 mmol) of the compound from example 27A in6 ml of DMF were added, at RT, 248 mg (1.53 mmol) ofN,N′-carbonyldiimidazole, and the mixture was stirred at bathtemperature 60° C. for 7 h. Subsequently, 100 ml each of water and ethylacetate were added to the mixture, the phases were separated and thenthe aqueous phase was extracted once with ethyl acetate. The combinedorganic phases were washed once with saturated sodium chloride solution,dried over sodium sulfate, filtered and concentrated. The residue wastaken up in dichloromethane and purified by means of columnchromatography (50 g of silica gel, eluent: cyclohexane/ethyl acetate7:3, Biotage). 344 mg (60% of theory, 100% purity) of the title compoundwere obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=8.5-8.0 (br. m, 1H), 8.10 (d, 1H),8.0-7.5 (br. m, 1H), 7.98 (dd, 1H), 7.84 (br. s, 1H), 7.64-7.49 (m, 3H),7.41-7.32 (m, 1H), 7.22 (br. s, 1H), 2.27-2.22 (m, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.16 min, m/z=410/412 [M+H]⁺.

Example 29A 6-Bromo-2-(2-fluorophenyl)-3-methylquinoline-4-carboxylicAcid

1.00 g (4.42 mmol) of 5-bromo-1H-indole-2,3-dione were initially chargedin 12.0 ml of acetic acid, and 673 mg (4.42 mmol) of1-(2-fluorophenyl)propan-1-one were added. The reaction mixture wasstirred at 75° C. for 5 min. Subsequently, 4.0 ml of conc. hydrochloricacid were added, and stirring of the mixture was continued at 105° C.overnight. After cooling to RT, the reaction mixture was added to 200 mlof 1 M hydrochloric acid and the precipitated solids were filtered off.The solids were washed with water, dried under reduced pressure and thenstirred with dichloromethane. The solvent was removed by suction and theresidue was dried under reduced pressure. 649 mg (37% of theory, 90%purity) of the title compound were obtained.

LC/MS (Method 1, ESIpos): R_(t)=0.90 min, m/z=360 [M+H]⁺.

Example 30A[6-Bromo-2-(2-fluorophenyl)-3-methylquinolin-4-yl](1H-imidazol-1-yl)methanone

To a solution of 500 mg (1.39 mmol) of the compound from example 29A in6 ml of DMF were added, at RT, 248 mg (1.53 mmol) ofN,N′-carbonyldiimidazole. The mixture was stirred at bath temperature60° C. for 5 h and then left to stand at RT for 14 h. Thereafter, afurther 124 mg (0.77 mmol) of N,N′-carbonyldiimidazole were added, andthe mixture was stirred at bath temperature 80° C. for 8 h and then leftto stand at RT for 14 h. Thereafter, another 162 mg (1.00 mmol) ofN,N′-carbonyldiimidazole were added, and the mixture was stirred at bathtemperature 100° C. for a further 7 h and then left to stand at RT for14 h. Thereafter, yet another 162 mg (1.00 mmol) ofN,N′-carbonyldiimidazole were added, and the mixture was stirred at bathtemperature 145° C. for a further 7 h and then left to stand at RT for14 h. Thereafter, still another 162 mg (1.00 mmol) ofN,N′-carbonyldiimidazole were added, and the mixture was stirred at bathtemperature 145° C. for a further 7 h and then left to stand at RT for14 h. Thereafter, once again another 162 mg (1.00 mmol) ofN,N′-carbonyldiimidazole were added, and the mixture was stirred at bathtemperature 145° C. for a further 7 h and then left to stand at RT for14 h. Thereafter, finally, 25 ml each of ethyl acetate and saturatedaqueous sodium chloride solution were added to the mixture, the phaseswere separated and then the aqueous phase was extracted twice with 50 mleach time of ethyl acetate. The combined organic phases were dried overmagnesium sulfate, filtered and concentrated. The residue was taken upin dichloromethane and purified by means of column chromatography (100 gof silica gel, eluent: cyclohexane/ethyl acetate 7:3, Biotage). 405 mg(71% of theory, 100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=8.5-7.5 (br. m, 2H), 8.11 (d, 1H), 8.00(dd, 1H), 7.87 (br. s, 1H), 7.67-7.56 (m, 2H), 7.45-7.36 (m, 2H), 7.21(br. s, 1H), 2.14 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.10 min, m/z=410/412 [M+H]⁺.

Example 31A 6-Bromo-3-methyl-2-(pyridin-4-yl)quinoline-4-carboxylic Acid

Method A:

1.00 g (4.42 mmol) of 5-bromo-1H-indole-2,3-dione were initially chargedin 12.0 ml of acetic acid, and 598 mg (4.42 mmol) of1-(pyridin-4-yl)propan-1-one were added. The reaction mixture wasstirred at 75° C. for 5 min. Subsequently, 4.0 ml of conc. hydrochloricacid were added, and stirring of the mixture was continued at 105° C.for 16 h. After cooling to RT, the reaction mixture was added to 200 mlof water and the precipitated solids were filtered off. The filtrate wasconcentrated under reduced pressure and the residue was purified bymeans of preparative HPLC (method 17). 200 mg (13% of theory, 100%purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=14.56 (br. s, 1H), 8.79-8.70 (m, 2H),8.08-8.01 (m, 1H), 7.98-7.92 (m, 2H), 7.66 (d, 2H), 2.40 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=0.45 min, m/z=343/345 [M+H]⁺.

Method B (General Experimental Procedure):

To a solution of the appropriate isatin (1H-indole-2,3-dione) in ethanol(concentration between 0.5 and 0.75 M) were added dropwise sixequivalents of an 8.5 M aqueous potassium hydroxide solution.Subsequently, one equivalent of 1-(pyridin-4-yl)propan-1-one was added,and the mixture was stirred under reflux overnight. After cooling to RTand removing the solvent under reduced pressure, the residue was takenup in water and the aqueous phase was extracted with ethyl acetate.Subsequently, the aqueous phase was adjusted to pH 4-5 by addinghydrochloric acid. The solids formed were filtered off, washed with alittle water and ethyl acetate, and dried under reduced pressure. Thetarget compound in question was obtained in a yield of 35-70% of theory.

Example 32A Ethyl 6-amino-2-chloro-5-fluoronicotinate

A mixture of 5.00 g (21.00 mmol) of ethyl2,6-dichloro-5-fluoronicotinate [described in US 2008/0171732, Example44 (b)] and 105 ml (210 mmol) of a 2 M solution of ammonia in ethanolwas divided between 5 microwave vessels and heated in a microwaveapparatus to 120° C. for 1.5 h. After cooling to RT, the solvent wasremoved, and ethyl acetate was added to the residue. The mixture waswashed once with water, and the aqueous phase was then extracted oncewith ethyl acetate. The combined organic phases were washed once withsaturated sodium chloride solution, dried over magnesium sulfate,filtered and concentrated. The crude product thus obtained was combinedwith the crude product from an experiment conducted analogously [amountof ethyl 2,6-dichloro-5-fluoronicotinate used: 1.00 g (4.20 mmol)]. Thismaterial was then purified by means of preparative HPLC [column: DaicelC18 Bio Spring Column, 10 μm, 300×100 mm; flow rate: 250 ml/min;detection: 210 nm; injection volume: 20 ml; temperature: 22° C.; eluent:acetonitrile/water gradient]. 2.60 g of the title compound were obtained(100% purity, 47% of theory based on a total of 6.0 g of ethyl2,6-dichloro-5-fluoronicotinate). Also obtained were 290 mg of theisomeric compound ethyl 2-amino-6-chloro-5-fluoronicotinate (100%purity, 5% of theory based on a total of 6.0 g of ethyl2,6-dichloro-5-fluoronicotinate).

¹H-NMR (500 MHz, DMSO-d₆): [ppm]=7.80 (d, 1H), 7.49 (br. s, 2H), 4.23(q, 2H), 1.28 (t, 3H).

LC/MS (Method 1, ESIpos): R_(t)=0.82 min, m/z=219 [M+H]⁺.

Example 33A Ethyl 6-amino-5-fluoronicotinate trifluoroacetic Acid Salt

A mixture, made up under argon, of 500 mg (2.29 mmol) of the compoundfrom example 32A, 100 mg (94 mmol) of palladium on activated carbon (10%Pd) and 324 mg (3.20 mmol) of triethylamine in 20 ml of ethanol washydrogenated under standard pressure at RT for 6 h. Subsequently, afurther 100 mg (94 mmol) of palladium on activated carbon (10% Pd) and324 mg (3.20 mmol) of triethylamine were added, and hydrogenation waseffected under standard pressure at RT for a further 16 h. Thereafter,another 100 mg (94 mmol) of palladium on activated carbon (10% Pd) and324 mg (3.20 mmol) of triethylamine were added, and hydrogenation waseffected under standard pressure at RT for another 6 h. Thereafter, themixture was filtered through kieselguhr, and the filter residue waswashed with ethanol and ethyl acetate. The filtrate was concentrated andthe residue was stirred with water. The solids present were filteredoff, washed with water and dried under reduced pressure. The crudeproduct obtained was purified by means of preparative HPLC (method 16).The combined product fractions were concentrated, and the residue wastaken up in dichloromethane, concentrated again and finally dried underreduced pressure. 555 mg (81% of theory, 100% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=8.37-8.35 (m, 1H), 7.69 (dd, 1H),7.4-5.5 (br. m, 2H), 4.25 (q, 2H), 1.29 (t, 3H).

LC/MS (Method 2, ESIpos): R_(t)=1.83 min, m/z=185 [M+H]⁺.

Example 34A Ethyl4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}benzoate

To 300 mg (0.88 mmol) of the compound from example 1A were added 16 mlof dichloromethane and then 0.19 ml (1.40 mmol) of1-chloro-N,N,2-trimethylprop-1-en-1-amine. The mixture was stirred at RTfor 30 min, and then 0.21 ml (2.63 mmol) of pyridine and 145 mg (0.88mmol) of ethyl 4-aminobenzoate, dissolved in 4 ml of dichloromethane,were added. The reaction mixture was then stirred at 50° C. for 30 minand then at 70° C. for 90 min. After cooling down to RT, the solvent wasremoved under reduced pressure, and the residue was purified by means ofpreparative HPLC (method 7) without further workup. 177 mg (41% oftheory, 100% purity) of the title compound were obtained.

LC/MS (Method 1, ESIpos): R_(t)=1.31 min, m/z=489/491 [M+H]+.

Example 35A4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}benzoylChloride

To a suspension of 200 mg (0.43 mmol) of the compound from Example 1 in5 ml of dichloromethane were successively added one drop of DMF and,gradually, 110 mg (0.87 mmol) of oxalyl chloride. After stirring at RTfor 1 h, a further 59 mg (0.46 mmol) of oxalyl chloride were added, andthe mixture was stirred at RT for another 30 min. Subsequently, themixture was concentrated and the residue was dried under reducedpressure. The title compound was obtained in a purity of 98% by LC/MS(the analytical sample was quenched with methanol).

LC/MS (Method 3, ESIpos): R_(t)=1.52 min, m/z=475/477 [M−Cl+OCH₃+H]⁺.

Example 36A Methyl5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}pyrimidine-2-carboxylate

150 mg (0.38 mmol) of the compound from example 2A and 59 mg (0.38 mmol)of methyl 5-aminopyrimidine-2-carboxylate were dissolved in 3 ml of DMF.The mixture was stirred at RT for 15 min. Subsequently, 64 mg (0.57mmol) of potassium tert-butoxide were added, and stirring of thereaction mixture was continued at RT overnight. Thereafter, the mixture,without further workup, was purified by means of preparative HPLC(method 6). After the solvent-water mixture had been removed, themixture was dried under reduced pressure overnight. 23 mg (12% oftheory, 95% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=11.63 (s, 1H), 9.32 (s, 2H), 8.11 (d,1H), 8.05 (d, 1H), 7.95 (dd, 1H), 7.70-7.59 (m, 2H), 7.59-7.49 (m, 3H),3.92 (s, 3H), 2.42 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.05 min, m/z=477/479 [M+H]⁺.

Example 37A Ethyl6-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-5-fluoronicotinate

To a solution of 200 mg (0.51 mmol) of the compound from example 2A and152 mg (0.51 mmol) of the compound from example 33A in 2 ml of DMF wereadded, in small portions at RT, 114 mg (1.02 mmol) of potassiumtert-butoxide. The mixture was stirred at RT for 15 min. Subsequently, afurther 29 mg (0.26 mmol) of potassium tert-butoxide were added in smallportions, and the mixture was stirred at RT for another 15 min.Thereafter, the mixture, without further workup, was purified by meansof preparative HPLC (method 5). 195 mg (74% of theory, 99% purity) ofthe title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.66 (s, 1H), 8.89 (br. s, 1H), 8.35(d, 1H), 8.09-7.91 (m, 3H), 7.67-7.49 (m, 5H), 4.39 (q, 2H), 2.47 (s,3H), 1.36 (t, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.18 min, m/z=508/510 [M+H]⁺.

Example 38A Methyl4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoate

1.00 g (2.55 mmol) of the compound from example 2A were dissolved in 10ml of DMF. To the solution were added 474 mg (2.80 mmol) of methyl4-amino-3-fluorobenzoate and 429 mg (3.82 mmol) of potassiumtert-butoxide. The reaction mixture was stirred at RT for 1 h and thenstirred into a mixture of 50 ml of ice-water, 50 ml of ammonium chloridesolution and 100 ml of ethyl acetate. The organic phase was removed,washed twice with water and once with saturated sodium chloridesolution, and dried over magnesium sulfate. The solvent was removedunder reduced pressure and the residue was purified by means of columnchromatography (silica gel, eluent: 5% ethyl acetate/95% cyclohexane→15%ethyl acetate/85% cyclohexane→45% ethyl acetate/55% cyclohexane,Biotage). The product-containing fractions were concentrated and theresidue was stirred in 10 ml of tert-butyl methyl ether. The solids werefiltered off, washed twice with 5 ml of tert-butyl methyl ether and thenstirred in 4 ml of ethyl acetate for three days. The solids were thenfiltered off again and dried under reduced pressure. 810 mg (64% oftheory, 99% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.10 (s, 1H), 8.27 (t, 1H), 8.05 (d,1H), 7.99 (d, 1H), 7.95-7.90 (m, 2H), 7.85 (dd, 1H), 7.64-7.62 (m, 2H),7.58-7.51 (m, 3H), 3.89 (s, 3H), 2.43 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.27 min, m/z=493/495 [M+H]⁺.

Example 39A tert-Butyl4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoate

To a mixture of 1.00 g (2.09 mmol) of the compound from Example 7 in 50ml of THF were added 912 mg (4.17 mmol) of tert-butyltrichloroacetimidate and 59 mg (0.42 mmol) of boron trifluoride-diethylether complex, and the mixture was stirred at RT for another 1 h.Subsequently, a further 912 mg (4.17 mmol) of tert-butyltrichloroacetimidate were added and the mixture was stirred under refluxfor another 1 h. After dichloromethane had been added, the mixture waswashed with water and the aqueous phase was extracted once withdichloromethane. The combined organic phases were washed once withsaturated sodium chloride solution, dried over magnesium sulfate,filtered and concentrated. The residue was purified by means of columnchromatography (silica gel, eluent: cyclohexane/ethyl acetate 85:15,Biotage). 939 mg (84% of theory, 100% purity) of the title compound wereobtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=11.06 (s, 1H), 8.22 (t, 1H), 8.05 (d,1H), 7.98 (d, 1H), 7.94 (dd, 1H), 7.85 (dd, 1H), 7.78 (dd, 1H),7.66-7.61 (m, 2H), 7.60-7.49 (m, 3H), 2.43 (s, 3H), 1.57 (s, 9H).

LC/MS (Method 1, ESIpos): R_(t)=1.41 min, m/z=535/537 [M+H]⁺.

Example 40A4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoylchloride

To a suspension of 250 mg (0.52 mmol) of the compound from Example 7 in2.5 ml of dichloromethane were successively added one drop of DMF and,gradually, 110 mg (0.87 mmol) of oxalyl chloride. After diluting with afurther 2.5 ml of dichloromethane and stirring at RT for 1 h, themixture was concentrated and the residue was dried under reducedpressure. The title compound was obtained in a purity of 94% by LC/MS(the analytical sample was quenched with methanol).

LC/MS (Method 3, ESIpos): R_(t)=1.55 min, m/z=493/495 [M−Cl+OCH₃+H]⁺.

Example 41A Methyl4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-fluorobenzoate

To 300 mg (0.88 mmol) of the compound from example 1A were added 3 ml ofdichloromethane and then 0.19 ml (1.40 mmol) of1-chloro-N,N,2-trimethylprop-1-en-1-amine. The mixture was stirred at RTfor 30 min, and then 0.21 ml (2.63 mmol) of pyridine and 148 mg (0.88mmol) of methyl 4-amino-2-fluorobenzoate were added. The reactionmixture was subsequently stirred at 70° C. for 3 h. After cooling downto RT, the solvent was removed under reduced pressure, and the residuewas purified by means of preparative HPLC (method 7) without furtherworkup. 124 mg (23% of theory, 81% purity) of the title compound wereobtained.

LC/MS (Method 1, ESIpos): R_(t)=1.27 min, m/z=493/495 [M+H]⁺.

Example 42A Methyl4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-chlorobenzoate

To a solution of 1.50 g (3.82 mmol) of the compound from example 2A and710 mg (3.82 mmol) of methyl 4-amino-3-chlorobenzoate in 15 ml of DMFwere added, in small portions at RT, 430 mg (3.82 mmol) of potassiumtert-butoxide. The mixture was stirred at RT for 15 min. Subsequently,another 215 mg (1.91 mmol) of potassium tert-butoxide were added insmall portions, and the mixture was stirred at RT for a further 2 h.Thereafter, the mixture was introduced into 40 ml of a 10% aqueouscitric acid solution while stirring, whereupon there was precipitationof solids. After diluting with water, the solids were filtered off,washed with water and dried under reduced pressure. The crude productthus obtained was purified by means of column chromatography (100 g ofsilica gel, eluent: cyclohexane/ethyl acetate 85:15, Biotage). 1.60 g(80% of theory, 98% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=10.96 (s, 1H), 8.14-8.08 (m, 3H),8.07-8.02 (m, 2H), 7.94 (dd, 1H), 7.66-7.61 (m, 2H), 7.60-7.50 (m, 3H),3.90 (s, 3H), 2.48 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.32 min, m/z=509/511 [M+H]⁺.

Example 43A Methyl3-bromo-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}benzoate

To a solution of 200 mg (0.51 mmol) of the compound from example 2A and129 mg (0.56 mmol) of methyl 4-amino-3-bromobenzoate in 2 ml of DMF wereadded, in small portions at RT, 57 mg (0.51 mmol) of potassiumtert-butoxide. The mixture was stirred at RT for 15 min. Subsequently,another 29 mg (0.26 mmol) of potassium tert-butoxide were added in smallportions, and the mixture was stirred at RT for a further 15 min.Thereafter, the mixture was admixed with 4 ml of a 10% aqueous citricacid solution, diluted with water and extracted twice with ethylacetate. The combined organic phases were washed once with saturatedsodium chloride solution, dried over magnesium sulfate, filtered andconcentrated. The residue was prepurified by means of columnchromatography (25 g of silica gel, eluent: cyclohexane/ethyl acetate85:15, Biotage) and then purified further by means of preparative HPLC(method 5). 145 mg (51% of theory, 100% purity) of the title compoundwere obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=10.91 (s, 1H), 8.25 (d, 1H), 8.14 (d,1H), 8.10-8.07 (m, 1H), 8.07-8.02 (m, 2H), 7.94 (dd, 1H), 7.66-7.61 (m,2H), 7.60-7.50 (m, 3H), 3.90 (s, 3H), 2.50 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.33 min, m/z=553/555/557 [M+H]⁺.

Example 44A Ethyl4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3,5-dichlorobenzoate

To a solution of 200 mg (0.51 mmol) of the compound from example 2A and119 mg (0.51 mmol) of ethyl 4-amino-3,5-dichlorobenzoate in 2 ml of DMFwere added, in small portions at RT, 57 mg (0.51 mmol) of potassiumtert-butoxide. The mixture was stirred at RT for 15 min. Subsequently,another 29 mg (0.26 mmol) of potassium tert-butoxide were added in smallportions, and the mixture was stirred at RT for a further 15 min.Thereafter, the mixture was purified directly by means of preparativeHPLC (method 5). The combined product-containing fractions wereneutralized with saturated sodium hydrogencarbonate solution andconcentrated down to a residual volume of aqueous phase. The solidsformed were filtered off, washed twice with water and dried underreduced pressure. 76 mg (24% of theory, 90% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.26 (s, 1H), 8.43-8.37 (m, 1H),8.13 (s, 1H), 8.09-8.02 (m, 1H), 7.99-7.92 (m, 1H), 7.73 (s, 1H),7.68-7.48 (m, 5H), 4.38 (q, 2H), 2.58 (s, 3H, partially hidden), 1.36(t, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.41 min, m/z=557/559/561 [M+H]⁺.

Example 45A Methyl4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-methylbenzoate

To 300 mg (0.88 mmol) of the compound from example 1A were added 3 ml ofdichloromethane and then 0.19 ml (1.40 mmol) of1-chloro-N,N,2-trimethylprop-1-en-1-amine. The mixture was stirred at RTfor 30 min, and then 0.21 ml (2.63 mmol) of pyridine and 145 mg (0.88mmol) of methyl 4-amino-3-methylbenzoate were added. The reactionmixture was subsequently stirred at 70° C. for 3 h. After cooling downto RT, the solvent was removed under reduced pressure, and the residuewas purified by means of preparative HPLC (method 7) without furtherworkup. 128 mg (25% of theory, 84% purity) of the title compound wereobtained.

LC/MS (Method 1, ESIpos): R_(t)=1.27 min, m/z=489/491 [M+H]⁺.

Example 46A Methyl4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-methoxybenzoate

To a solution of 820 mg (2.09 mmol) of the compound from example 2A and379 mg (2.09 mmol) of methyl 4-amino-3-methoxybenzoate in 8 ml of DMFwere added, in small portions at RT, 235 mg (2.09 mmol) of potassiumtert-butoxide. The mixture was stirred at RT for 15 min. Subsequently,another 117 mg (1.05 mmol) of potassium tert-butoxide were added insmall portions, and the mixture was stirred at RT for a further 2 h.Thereafter, the mixture was introduced into 20 ml of a 10% aqueouscitric acid solution while stirring, whereupon there was precipitationof solids. After diluting with water, the solids were filtered off,washed with water and dried under reduced pressure. The crude productthus obtained was purified by means of column chromatography (50 g ofsilica gel, eluent: cyclohexane/ethyl acetate 85:15, Biotage). 709 mg(67% of theory, 100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=10.53 (s, 1H), 8.17 (d, 1H), 8.06-8.00(m, 2H), 7.92 (dd, 1H), 7.69 (dd, 1H), 7.65-7.60 (m, 3H), 7.59-7.47 (m,3H), 3.94 (s, 3H), 3.89 (s, 3H), 2.42 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.25 min, m/z=505/507 [M+H]+.

Example 47A Ethyl4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(trifluoromethoxy)benzoate

150 mg (0.38 mmol) of the compound from example 2A and 95 mg (0.38 mmol)of ethyl 4-amino-3-(trifluoromethoxy)benzoate were dissolved in 3 ml ofDMF. 86 mg (0.76 mmol) of potassium tert-butoxide were added, and themixture was stirred at RT for 15 min. Thereafter, a further 22 mg (0.19mmol) of potassium tert-butoxide were added gradually. Stirring of thereaction mixture continued at RT overnight, and then it was purified,without further workup, by means of preparative HPLC (method 6). Afterthe solvent-water mixture had been removed, the residue was dried underreduced pressure overnight. 75 mg (34% of theory, 100% purity) of thetitle compound were obtained.

LC/MS (Method 1, ESIpos): R_(t)=1.38 min, m/z=573/575 [M+H]⁺.

Example 48A Methyl4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(methylsulfanyl)benzoate

To a solution of 500 mg (1.28 mmol) of the compound from example 2A and267 mg (1.28 mmol, 94% purity) of methyl4-amino-3-(methylsulfanyl)benzoate [described in Org. Prep. Proced. Int.2003, 35 (5), 520-524] in 5 ml of DMF were added, in small portions atRT, 144 mg (1.28 mmol) of potassium tert-butoxide. The mixture wasstirred at RT for 15 min. Subsequently, a further 72 mg (0.64 mmol) ofpotassium tert-butoxide were added in small portions, and the mixturewas stirred at RT for a further 15 min. Thereafter, the mixture wasadmixed with 10 ml of a 10% aqueous citric acid solution, diluted withwater and extracted twice with ethyl acetate. The combined organicphases were washed once with saturated sodium chloride solution, driedover magnesium sulfate, filtered and concentrated. The residue waspurified by means of column chromatography (50 g of silica gel, eluent:cyclohexane/ethyl acetate 85:15, Biotage). 418 mg (61% of theory, 96%purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.73 (s, 1H), 8.26 (d, 1H), 8.04 (d,1H), 7.96-7.91 (m, 2H), 7.88 (dd, 1H), 7.74 (d, 1H), 7.65-7.61 (m, 2H),7.60-7.49 (m, 3H), 3.90 (s, 3H), 2.57 (s, 3H), 2.52-2.50 (m, 3H,hidden).

LC/MS (Method 1, ESIpos): R_(t)=1.27 min, m/z=521/523 [M+H]⁺.

Example 49A Methyl4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(methylsulfinyl)benzoate

To a solution of 150 mg (0.29 mmol) of the compound from example 48A in3 ml of dichloromethane were added 71 mg (0.29 ml, 70% purity) of3-chloroperbenzoic acid, and the mixture was stirred at RT for 5 min.Subsequently, a further 20 mg (0.08 mmol) of 3-chloroperbenzoic acidwere added, and the mixture was stirred at RT for a further 5 min.Thereafter, another 20 mg (0.08 mmol) of 3-chloroperbenzoic acid wereadded, and the mixture was stirred at RT for another 5 min.Subsequently, the solvent was removed. The residue was taken up inacetonitrile and purified by means of preparative HPLC (method 5). Thecombined product-containing fractions were concentrated, and the residuewas taken up in dichloromethane, concentrated again and then dried underreduced pressure. 150 mg (97% of theory, 100% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.24 (s, 1H), 8.54 (d, 1H), 8.22(dd, 1H), 8.09-8.04 (m, 2H), 8.01-7.93 (m, 1H), 7.86 (d, 1H), 7.67-7.62(m, 2H), 7.61-7.49 (m, 3H), 3.93 (s, 3H), 2.92 (s, 3H), 2.50 (s, 3H,hidden).

LC/MS (Method 1, ESIpos): R_(t)=1.13 min, m/z=537/539 [M+H]⁺.

Example 50A Methyl4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(methylsulfonyl)benzoate

Method A:

To a solution of 150 mg (0.29 mmol) of the compound from example 48A in3 ml of dichloromethane were added 141 mg (0.58 mmol, 70% purity) of3-chloroperbenzoic acid. The mixture was stirred at RT for 30 min.Subsequently, the mixture was admixed with 5 ml of 1 M sodium hydroxidesolution, diluted with water and extracted three times withdichloromethane. The combined organic phases were washed once withsaturated sodium chloride solution, dried over magnesium sulfate,filtered and concentrated. After the residue had been dried underreduced pressure, 106 mg (61% of theory, 92% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.76 (s, 1H), 8.55 (d, 1H),8.42-8.32 (m, 2H), 8.26 (d, 1H), 8.04 (d, 1H), 7.94 (dd, 1H), 7.66-7.61(m, 2H), 7.59-7.49 (m, 3H), 3.94 (s, 3H), 3.42 (s, 3H), 2.50-2.48 (m,3H, hidden).

LC/MS (Method 1, ESIpos): R_(t)=1.23 min, m/z=553/555 [M+H]⁺.

Method B:

To a solution of 1.00 g (1.86 mmol) of the compound from example 49A in20 ml of dichloromethane were added 917 mg (3.72 mmol, 70% purity) of3-chloroperbenzoic acid. The mixture was stirred at RT for 2 h.Subsequently, the mixture was admixed with 35 ml of 1 M sodium hydroxidesolution, diluted with water and extracted three times withdichloromethane. The combined organic phases were washed once withsaturated sodium chloride solution, dried over magnesium sulfate,filtered and concentrated. After the residue had been dried underreduced pressure, 881 mg (67% of theory, 78% purity) of the titlecompound were obtained.

Example 51A Methyl4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-5-(ethylsulfonyl)-2-methoxybenzoate

To a solution of 200 mg (0.51 mmol) of the compound from example 2A and139 mg (0.51 mmol) of methyl 4-amino-5-(ethylsulfonyl)-2-methoxybenzoatein 2 ml of DMF were added, in small portions at RT, 57 mg (0.51 mmol) ofpotassium tert-butoxide, and the mixture was stirred at RT for 15 min.Subsequently, a further 29 mg (0.26 mmol) of potassium tert-butoxidewere added in small portions, and the mixture was stirred at RT foranother 15 min. Thereafter, the mixture was purified by means ofpreparative HPLC (method 5). The combined product-containing fractionswere neutralized with saturated sodium hydrogencarbonate solution andconcentrated down to a residual volume of aqueous phase. The solidsformed were filtered off, washed twice with water and dried underreduced pressure. 235 mg (77% of theory, 100% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.61 (s, 1H), 8.25 (br. s, 2H), 8.18(br. s, 1H), 8.08-8.01 (m, 1H), 7.98-7.90 (m, 1H), 7.68-7.60 (m, 2H),7.54 (s, 3H), 4.03 (s, 3H), 3.85 (s, 3H), 3.44 (q, 2H), 2.50 (s, 3H,hidden), 1.14 (t, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.32 min, m/z=597/599 [M+H]⁺.

Example 52A Dimethyl3,3′-disulfanediylbis(4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}benzoate)

To a mixture of 2.24 g (4.17 mmol) of the compound from example 49A and1.38 g (12.92 mmol) of 2,6-dimethylpyridine in 18.5 ml of acetonitrilewere added dropwise, at −20° C., 2.63 g (12.50 mmol) of trifluoroaceticanhydride. The mixture was stirred at −10° C. to 0° C. for 1 h.Thereafter, the mixture was concentrated under reduced pressure, and theresidue was admixed at 0° C. with 14 ml of a mixture of methanol andtriethylamine (1:1) which had been degassed and cooled to 0° C.Subsequently, the mixture was stirred at RT for 30 min and then thevolatile constituents were removed under reduced pressure. The residuewas admixed with 4 ml of a mixture of methanol and 6 M hydrochloricacid, and stirred at 50° C. for 20 min. Subsequently, the mixture wasconcentrated, the residue was taken up in ethyl acetate and the mixturewas washed once with water. The aqueous phase was reextracted once withethyl acetate. The combined organic phases were washed once withsaturated sodium chloride solution, dried over magnesium sulfate,filtered and concentrated. The residue was taken up in dichloromethane,applied to 10 g of neutral alumina and purified by column chromatography(silica gel, cyclohexane/ethyl acetate 7:3, Biotage, with pre-column).Fractions that contained the title compound were obtained, as werefurther fractions that contained the compound listed as example 72A as aby-product of the reaction. The fractions that contained the titlecompound were concentrated and the residue was stirred in acetonitrile.The solids present were filtered off and dried under reduced pressure.In this way, 608 mg (13% of theory, about 90% purity) of the titlecompound were obtained.

LC/MS (Method 1, ESIpos): R_(t)=1.59 min, m/z=1011/1013/1015 [M+H]⁺.

The fractions that contained the compound listed as example 72A wereconcentrated and purified further by means of preparative HPLC (column:Sunfire C18, 5 μm, 100 mm×30 mm; eluent: water/acetonitrile/2% formicacid in water; gradient: 50:30:20-5:90:5, 10 min; injection volume: 1.0ml; flow rate: 75 ml/min; temperature: 40° C.; detection: 210 nm). 210mg (9% of theory, 100% purity) of the by-product were obtained (foranalysis see example 72A).

Example 53A Methyl4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-[(trifluoromethyl)sulfanyl]benzoate

To a mixture of 300 mg (0.30 mmol, 90% purity) of the compound fromexample 52A in 3 ml of DMF were added 105 mg (0.89 mmol) of sodiumhydroxymethanesulfinate (Rongalit™), and the mixture was stirred at RTfor 15 min. Subsequently, 196 mg (0.59 mmol) of3,3-dimethyl-1-(trifluoromethyl)-1,2-benzodioxole were added, and themixture was stirred at RT for a further 30 min. Thereafter, the mixture,without further workup, was purified by means of preparative HPLC(method 5). 140 mg (91% of theory, 100% purity) of the title compoundwere obtained.

LC/MS (Method 1, ESIpos): R_(t)=1.40 min, m/z=575/577 [M+H]⁺.

An experiment conducted analogously gave the following ¹H NMR of thetitle compound [amount of compound from example 52A used: 100 mg (0.10mmol)]:

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=11.37 (s, 1H), 8.36 (s, 1H), 8.28 (dd,1H), 8.16 (d, 1H), 8.06 (d, 1H), 8.00-7.92 (m, 2H), 7.67-7.61 (m, 2H),7.60-7.49 (m, 3H), 3.92 (s, 3H), 2.47 (s, 3H).

Example 54A Methyl3-fluoro-4-{[(6-fluoro-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}benzoate

To a solution of 200 mg (0.60 mmol) of the compound from example 4A and102 mg (0.60 mmol) of methyl 4-amino-3-fluorobenzoate in 2.5 ml of DMFwere added, in small portions at RT, 68 mg (0.60 mmol) of potassiumtert-butoxide, and the mixture was stirred at RT for 15 min.Subsequently, a further 34 mg (0.31 mmol) of potassium tert-butoxidewere added in small portions, and the mixture was stirred at RT for afurther 15 min. Thereafter, the mixture was admixed with 4 ml of a 10%aqueous citric acid solution, diluted with water and extracted twicewith ethyl acetate. The combined organic phases were washed once withsaturated sodium chloride solution, dried over magnesium sulfate,filtered and concentrated. The residue was purified by means of columnchromatography (25 g of silica gel, eluent: cyclohexane/ethyl acetate85:15, Biotage). 198 mg (76% of theory, 100% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=11.07 (s, 1H), 8.28 (t, 1H), 8.17 (dd,1H), 7.91 (d, 1H), 7.84 (dd, 1H), 7.73 (td, 1H), 7.65-7.59 (m, 2H),7.59-7.47 (m, 4H), 3.89 (s, 3H), 2.43 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.16 min, m/z=433 [M+H]⁺.

Example 55A Methyl4-{[(3,6-dimethyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoate

To a solution of 200 mg (0.61 mmol) of the compound from example 8A and103 mg (0.61 mmol) of methyl 4-amino-3-fluorobenzoate in 2.4 ml of DMFwere added, in small portions at RT, 69 mg (0.61 mmol) of potassiumtert-butoxide, and the mixture was stirred at RT for 15 min.Subsequently, a further 34 mg (0.30 mmol) of potassium tert-butoxidewere added in small portions, and the mixture was stirred at RT for afurther 15 min. Thereafter, 21 mg (0.12 mmol) of methyl4-amino-3-fluorobenzoate and 14 mg (0.12 mmol) of potassiumtert-butoxide were added, and the mixture was stirred at RT for another30 min. Subsequently, the mixture was admixed with 4 ml of a 10% aqueouscitric acid solution, diluted with water and extracted twice with ethylacetate. The combined organic phases were washed once with saturatedsodium chloride solution, dried over magnesium sulfate, filtered andconcentrated. The residue was purified by means of preparative HPLC(Method 5). The combined product-containing fractions were concentrated,and the residue was taken up in dichloromethane, concentrated again andthen dried under reduced pressure. 134 mg (47% of theory, 92% purity) ofthe title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=11.06 (s, 1H), 8.31 (t, 1H), 8.00 (d,1H), 7.91 (dd, 1H), 7.84 (dd, 1H), 7.67 (dd, 1H), 7.65-7.60 (m, 3H),7.59-7.48 (m, 3H), 3.89 (s, 3H), 2.41 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.16 min, m/z=429 [M+H]⁺.

Example 56A Methyl4-{[(6-ethyl-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoate

To a solution of 200 mg (0.59 mmol) of the compound from example 10A and99 mg (0.59 mmol) of methyl 4-amino-3-fluorobenzoate in 2 ml of DMF wereadded, in small portions at RT, 66 mg (0.59 mmol) of potassiumtert-butoxide, and the mixture was stirred at RT for 15 min.Subsequently, a further 29 mg (0.26 mmol) of potassium tert-butoxidewere added in small portions, and the mixture was stirred at RT for afurther 15 min. Thereafter, 40 mg (0.12 mmol) of the compound fromexample 10A and 20 mg (0.12 mmol) of methyl 4-amino-3-fluorobenzoatewere added, and the mixture was stirred at RT for another 30 min.Subsequently, the mixture was admixed with 4 ml of a 10% aqueous citricacid solution, diluted with water and extracted twice with ethylacetate. The combined organic phases were washed once with saturatedsodium chloride solution, dried over magnesium sulfate, filtered andconcentrated. The residue was purified by means of preparative HPLC(Method 5). The combined product-containing fractions were concentrated,and the residue was taken up in dichloromethane, concentrated again andthen dried under reduced pressure. 195 mg (69% of theory, 91% purity) ofthe title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=11.06 (s, 1H), 8.26 (t, 1H), 8.03 (d,1H), 7.92 (dd, 1H), 7.85 (dd, 1H), 7.72 (dd, 1H), 7.66-7.60 (m, 3H),7.59-7.48 (m, 3H), 3.92-3.87 (m, 3H), 2.84 (q, 2H), 2.41 (s, 3H), 1.26(t, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.25 min, m/z=443 [M+H]+.

Example 57A Methyl3-fluoro-4-{[(6-isopropyl-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}benzoate

To 670 mg (2.19 mmol) of the compound from example 11A were added 3 mlof dichloromethane and then 0.46 ml (3.51 mmol) of1-chloro-N,N,2-trimethylprop-1-en-1-amine. The mixture was stirred at RTfor 30 min, and then 0.53 ml (6.55 mmol) of pyridine and 371 mg (2.19mmol) of methyl 4-amino-3-fluorobenzoate were added. The reactionmixture was stirred at 60° C. for 10 h. After cooling down to RT, thesolvent was removed under reduced pressure, and the residue was purifiedby means of preparative HPLC (method 8) without further workup. 108 mg(10% of theory, 96% purity) of the title compound were obtained.

LC/MS (Method 1, ESIpos): R_(t)=1.32 min, m/z=457 [M+H]⁺.

Example 58A Methyl3-fluoro-4-({[3-methyl-2-phenyl-6-(trifluoromethyl)quinolin-4-yl]carbonyl}amino)benzoate

To 300 mg (0.91 mmol) of the compound from example 12A were added 2 mlof dichloromethane and then 0.19 ml (1.45 mmol) of1-chloro-N,N,2-trimethylprop-1-en-1-amine. The mixture was stirred at RTfor 30 min, and then 0.22 ml (2.72 mmol) of pyridine and 153 mg (0.91mmol) of methyl 4-amino-3-fluorobenzoate were added. The reactionmixture was stirred at 60° C. for 4 h. After cooling down to RT, thesolvent was removed under reduced pressure, and the residue was purifiedby means of preparative HPLC (method 7) without further workup. 105 mg(20% of theory, 83% purity) of the title compound were obtained.

LC/MS (Method 1, ESIpos): R_(t)=0.91 min, m/z=483 [M+H]⁺.

Example 59A Methyl3-fluoro-4-({[3-methyl-2-phenyl-6-(trifluoromethoxy)quinolin-4-yl]carbonyl}amino)benzoate

To a solution of 200 mg (0.50 mmol) of the compound from example 14A and85 mg (0.50 mmol) of methyl 4-amino-3-fluorobenzoate in 2 ml of DMF wereadded, in small portions at RT, 56 mg (0.50 mmol) of potassiumtert-butoxide, and the mixture was stirred at RT for 15 min.Subsequently, a further 28 mg (0.26 mmol) of potassium tert-butoxidewere added in small portions, and the mixture was stirred at RT for afurther 15 min. Thereafter, the mixture was admixed with 4 ml of a 10%aqueous citric acid solution, diluted with water and extracted twicewith ethyl acetate. The combined organic phases were washed once withsaturated sodium chloride solution, dried over magnesium sulfate,filtered and concentrated. The residue was purified by means of columnchromatography (25 g of silica gel, eluent: cyclohexane/ethyl acetate85:15, Biotage). The combined product-containing fractions wereconcentrated, and the residue was taken up in dichloromethane,concentrated again and then dried under reduced pressure. 166 mg (60% oftheory, 91% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=11.11 (s, 1H), 8.27-8.17 (m, 2H), 7.92(dd, 1H), 7.86 (dd, 1H), 7.82 (dd, 1H), 7.75-7.73 (m, 1H), 7.66-7.61 (m,2H), 7.60-7.44 (m, 4H), 6.77 (t, 1H), 3.89 (s, 3H), 2.45 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.26 min, m/z=499 [M+H]⁺.

Example 60A tert-Butyl3-fluoro-4-({[3-methyl-2-phenyl-6-(trimethylsilyl)quinolin-4-yl]carbonyl}amino)benzoate

To a mixture of 214 mg (0.40 mmol) of the compound from example 39A and64 mg (0.44 mmol) of hexamethyldisilane in a mixture of 1 ml of tolueneand 1 ml of water were added 7 mg (0.02 mmol) of allyl palladiumchloride dimer, 11 mg (0.04 mmol) of (2-hydroxyphenyl)diphenylphosphine,19 mg (0.48 mmol) of sodium hydroxide and 14 mg (0.044 mmol) oftetrabutylammonium bromide. The mixture was stirred at 100° C. for 5 hand then left to stand at RT for 14 h. Subsequently, a further 64 mg(0.44 mmol) of hexamethyldisilane, 7 mg (0.02 mmol) of allyl palladiumchloride dimer and 11 mg (0.04 mmol) of(2-hydroxyphenyl)diphenylphosphine were added, and the mixture wasstirred at 100° C. for another 7 h. After then being left to stand at RTfor three days, the mixture was diluted with ethyl acetate and washedwith water. The aqueous phase was re-extracted once with ethyl acetate,and the combined organic phases were washed with saturated sodiumchloride solution, dried over magnesium sulfate, filtered andconcentrated. The residue was purified by means of preparative HPLC(method 5). The combined product-containing fractions were concentrated,and the residue was taken up in dichloromethane, concentrated again andthen dried under reduced pressure. In this way, 39 mg (18% of theory,100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.03 (s, 1H), 8.10-7.99 (m, 3H),7.94 (dd, 1H), 7.85 (dd, 1H), 7.80 (dd, 1H), 7.66-7.60 (m, 2H),7.59-7.48 (m, 3H), 2.43 (s, 3H), 1.57 (s, 9H), 0.32 (s, 9H).

LC/MS (Method 1, ESIpos): R_(t)=1.51 min, m/z=529 [M+H]⁺.

Example 61A Methyl4-({[6-bromo-3-(bromomethyl)-2-phenylquinolin-4-yl]carbonyl}amino)-3-fluorobenzoate

To a solution of 1.07 g (2.17 mmol) of the compound from Example 38A in10 ml of acetonitrile under argon were added, at RT, 463 mg (2.60 mmol)of N-bromosuccinimide (NBS) and 36 mg (0.22 mmol) of2,2′-azobis(2-methylpropionitrile) (AIBN), and the mixture was heated tobath temperature 80° C. Then 10 ml of carbon tetrachloride were added,and the mixture was stirred at bath temperature 80° C. for 1 h.Subsequently, a further 232 mg (1.30 mmol) of N-bromosuccinimide (NBS)and 21 mg (0.13 mmol) of 2,2′-azobis(2-methylpropionitrile) (AIBN) wereadded, and the mixture was stirred at bath temperature 80° C. for afurther 8 h. After cooling to RT, the solids present were filtered offand washed twice with 2 ml of acetonitrile. After the solids had beendried under reduced pressure, 656 mg (44% of theory, 84% purity) of afirst batch of the title compound were obtained. The filtrate wasconcentrated and the residue was purified by means of columnchromatography (silica gel, eluent: cyclohexane/ethyl acetate 9:1)together with a residue obtained analogously from a preceding experiment[amount of compound from example 38A used: 100 mg (0.20 mmol)]. In thisway, 260 mg of a second batch of the title compound were obtained (90%purity, 17% of theory, based on a total of 1.17 g (2.37 mmol) of theamount of compound from example 38A used). Additionally obtained as aby-product of the reaction were 194 mg (10% of theory, 70% purity) ofthe compound from example 62A (see therein).

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=11.23 (s, 1H), 8.25 (t, 1H), 8.10-8.01(m, 3H), 7.93 (dd, 1H), 7.87 (dd, 1H), 7.72-7.66 (m, 2H), 7.64-7.56 (m,3H), 4.73 (dd, 2H), 3.90 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.27 min, m/z=571/573/575 [M+H]⁺.

Example 62A Methyl4-({[6-bromo-3-(dibromomethyl)-2-phenylquinolin-4-yl]carbonyl}amino)-3-fluorobenzoate

The title compound (194 mg, 70% purity) was obtained as a by-product ofthe reaction described in example 61A.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=11.26 (s, 1H), 8.38 (t, 1H), 8.14-8.07(m, 3H), 7.94 (dd, 1H), 7.87 (dd, 1H), 7.65-7.59 (m, 5H), 7.03 (s, 1H),3.90 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.32 min, m/z=649/651/653/655 [M+H]⁺.

Example 63A Methyl4-({[6-bromo-3-(fluoromethyl)-2-phenylquinolin-4-yl]carbonyl}amino)-3-fluorobenzoate

To a mixture of 232 mg (0.37 mmol, 90% purity) of the compound fromexample 61A in 18 ml of acetonitrile under argon were added 130 mg (1.02mmol) of silver fluoride, and the mixture was heated at bath temperature80° C. for 1.5 h. After cooling to RT, the mixture was admixed with 100ml each of ethyl acetate and saturated aqueous sodium hydrogencarbonatesolution. After phase separation, the aqueous phase was extracted oncewith ethyl acetate. The combined organic phases were dried over sodiumsulfate, filtered and concentrated. The residue was taken up indichloromethane and purified by means of column chromatography (25 g ofsilica gel, eluent: cyclohexane/ethyl acetate 9:1, Biotage). In thisway, 77 mg (41% of theory, 100% purity) of the title compound wereobtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.19 (s, 1H), 8.28 (t, 1H),8.15-8.10 (m, 2H), 8.07 (dd, 1H), 7.93 (dd, 1H), 7.86 (dd, 1H),7.70-7.64 (m, 2H), 7.62-7.54 (m, 3H), 5.63 (s, 1H), 5.51 (s, 1H), 3.89(s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.22 min, m/z=511/513 [M+H]⁺.

Example 64A Methyl4-({[6-bromo-3-(difluoromethyl)-2-phenylquinolin-4-yl]carbonyl}amino)-3-fluorobenzoate

To a mixture of 170 mg (0.18 mmol, 70% purity) of the compound fromexample 62A in 6 ml of acetonitrile under argon were added 93 mg (0.73mmol) of silver fluoride, and the mixture was heated at bath temperature80° C. for 1 h. After cooling to RT, the mixture was admixed with 50 mleach of ethyl acetate and saturated aqueous sodium hydrogencarbonatesolution. After phase separation, the aqueous phase was extracted oncewith 50 ml of ethyl acetate. The combined organic phases were dried oversodium sulfate, filtered and concentrated. The residue was taken up indichloromethane and purified by means of column chromatography (25 g ofsilica gel, eluent: cyclohexane/ethyl acetate 9:1, Biotage). In thisway, 28 mg (27% of theory, 95% purity) of the title compound wereobtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.16 (s, 1H), 8.34-8.28 (m, 1H),8.17-8.11 (m, 3H), 7.92 (dd, 1H), 7.85 (dd, 1H), 7.65-7.55 (m, 5H), 7.08(t, 1H), 3.89 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.22 min, m/z=529/531 [M+H]+.

Example 65A Methyl4-{[(6-bromo-3-ethyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoate

To a solution of 238 mg (0.59 mmol) of the compound from example 16A and99 mg (0.59 mmol) of methyl 4-amino-3-fluorobenzoate in 2.3 ml of DMFunder argon was added 0.88 ml (0.88 mmol) of a 1 M solution of potassiumtert-butoxide in THF, and the mixture was stirred at RT for 1 h.Subsequently, the mixture was admixed with 4 ml of a 10% aqueous citricacid solution, diluted with water and extracted twice with 20 ml eachtime of ethyl acetate. The combined organic phases were washed once with40 ml of saturated sodium chloride solution, dried over sodium sulfate,filtered and concentrated. The residue was taken up in dichloromethaneand purified by means of column chromatography (50 g of silica gel,eluent: cyclohexane/ethyl acetate 4:1, Biotage). 206 mg (69% of theory,100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=11.13 (s, 1H), 8.22 (t, 1H), 8.06-7.89(m, 4H), 7.85 (dd, 1H), 7.60-7.49 (m, 5H), 3.89 (s, 3H), 2.91-2.76 (m,2H), 0.98 (t, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.27 min, m/z=507/509 [M+H]⁺.

Example 66A Methyl4-{[(6-bromo-2-phenyl-3-propylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoate

To a solution of 170 mg (0.40 mmol) of the compound from example 18A and68 mg (0.40 mmol) of methyl 4-amino-3-fluorobenzoate in 2 ml of DMFunder argon was added 0.61 ml (0.61 mmol) of a 1 M solution of potassiumtert-butoxide in THF, and the mixture was stirred at RT for 1 h.Subsequently, the mixture was admixed with 4 ml of a 10% aqueous citricacid solution, diluted with water and extracted twice with 20 ml eachtime of ethyl acetate. The combined organic phases were washed once with40 ml of saturated sodium chloride solution, dried over sodium sulfate,filtered and concentrated. The residue was taken up in dichloromethaneand purified by means of column chromatography (25 g of silica gel,eluent: cyclohexane/ethyl acetate 9:1, Biotage). 151 mg (72% of theory,100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=11.11 (s, 1H), 8.18 (t, 1H), 8.03 (d,1H), 7.99 (d, 1H), 7.97-7.90 (m, 2H), 7.86 (dd, 1H), 7.59-7.50 (m, 5H),3.89 (s, 3H), 2.79 (t, 2H), 1.47-1.30 (m, 2H), 0.67 (t, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.31 min, m/z=521/523 [M+H]⁺.

Example 67A Methyl4-{[(6-bromo-7-chloro-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoate

To a solution of 200 mg (0.47 mmol) of the compound from example 20A and87 mg (0.52 mmol) of methyl 4-amino-3-fluorobenzoate in 1 ml of DMFunder argon were added, in small portions at RT, 53 mg (0.47 mmol) ofpotassium tert-butoxide, and the mixture was stirred at RT for 15 min.Subsequently, a further 26 mg (0.24 mmol) of potassium tert-butoxidewere added in small portions, and the mixture was stirred at RT foranother 15 min. Thereafter, the mixture was admixed with 4 ml of a 10%aqueous citric acid solution and diluted with 6 ml of water. The solidsformed were filtered off, washed twice with water and dried underreduced pressure. The solids were then taken up in dichloromethane andpurified by means of column chromatography (50 g of silica gel, eluent:cyclohexane/ethyl acetate 9:1, Biotage). 74 mg (30% of theory, 100%purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=11.11 (s, 1H), 8.39 (s, 1H), 8.28 (t,1H), 8.20 (s, 1H), 7.92 (dd, 1H), 7.85 (dd, 1H), 7.66-7.61 (m, 2H),7.60-7.49 (m, 3H), 3.89 (s, 3H), 2.43 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.32 min, m/z=527/529 [M+H]+.

Example 68A Methyl4-({[6-bromo-2-(4-fluorophenyl)-3-methylquinolin-4-yl]carbonyl}amino)-3-fluorobenzoate

To a solution of 200 mg (0.49 mmol) of the compound from example 26A and82 mg (0.49 mmol) of methyl 4-amino-3-fluorobenzoate in 2 ml of DMFunder argon was added 0.73 ml (0.73 mmol) of a 1 M solution of potassiumtert-butoxide in THF, and the mixture was stirred at RT for 1 h.Subsequently, the mixture was admixed with 4 ml of a 10% aqueous citricacid solution, diluted with water and extracted twice with 20 ml eachtime of ethyl acetate. The combined organic phases were washed once with40 ml of saturated sodium chloride solution, dried over sodium sulfate,filtered and concentrated. The residue was taken up in dichloromethaneand purified by means of column chromatography (50 g of silica gel,eluent: cyclohexane/ethyl acetate 4:1, Biotage). 193 mg (77% of theory,100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=11.08 (s, 1H), 8.27 (t, 1H), 8.05 (d,1H), 8.00-7.97 (m, 1H), 7.96-7.88 (m, 2H), 7.85 (dd, 1H), 7.73-7.65 (m,2H), 7.38 (t, 2H), 3.89 (s, 3H), 2.43 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.25 min, m/z=511/513 [M+H]+.

Example 69A Methyl4-({[6-bromo-2-(3-fluorophenyl)-3-methylquinolin-4-yl]carbonyl}amino)-3-fluorobenzoate

To a solution of 170 mg (0.41 mmol) of the compound from example 28A and70 mg (0.41 mmol) of methyl 4-amino-3-fluorobenzoate in 2 ml of DMFunder argon was added 0.62 ml (0.62 mmol) of a 1 M solution of potassiumtert-butoxide in THF, and the mixture was stirred at RT for 1 h.Subsequently, the mixture was admixed with 4 ml of a 10% aqueous citricacid solution, diluted with water and extracted twice with 20 ml eachtime of ethyl acetate. The combined organic phases were dried oversodium sulfate, filtered and concentrated. The residue was taken up indichloromethane and purified by means of column chromatography (25 g ofsilica gel, eluent: cyclohexane/ethyl acetate 9:1, Biotage). 108 mg (51%of theory, 100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=11.09 (s, 1H), 8.27 (t, 1H), 8.06 (d,1H), 8.01-7.90 (m, 3H), 7.85 (dd, 1H), 7.66-7.55 (m, 1H), 7.51-7.44 (m,2H), 7.41-7.33 (m, 1H), 3.89 (s, 3H), 2.44 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.25 min, m/z=511/513 [M+H]⁺.

Example 70A Methyl4-({[6-bromo-2-(2-fluorophenyl)-3-methylquinolin-4-yl]carbonyl}amino)-3-fluorobenzoate

To a solution of 200 mg (0.49 mmol) of the compound from example 30A and82 mg (0.49 mmol) of methyl 4-amino-3-fluorobenzoate in 2.4 ml of DMFunder argon was added 0.73 ml (0.73 mmol) of a 1 M solution of potassiumtert-butoxide in THF, and the mixture was stirred at RT for 1 h.Subsequently, the mixture was admixed with 4 ml of a 10% aqueous citricacid solution, diluted with water and extracted twice with 20 ml eachtime of ethyl acetate. The combined organic phases were dried oversodium sulfate, filtered and concentrated. The residue was admixed with4 ml of acetonitrile and the mixture was treated in an ultrasound bath,whereupon there was precipitation of solids. The solids were filteredoff, washed with 4 ml of acetonitrile and dried under reduced pressure.164 mg (63% of theory, 96% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=11.18 (s, 1H), 8.25 (t, 1H), 8.09-8.04(m, 1H), 8.02 (d, 1H), 7.99-7.94 (m, 1H), 7.91 (dd, 1H), 7.85 (dd, 1H),7.66-7.57 (m, 1H), 7.57-7.50 (m, 1H), 7.45-7.37 (m, 2H), 3.89 (s, 3H),2.32 (s, 3H).

LC/MS (Method 3, ESIpos): R_(t)=1.54 min, m/z=511/513 [M+H]⁺.

Example 71A Ethyl4-({[6-bromo-3-methyl-2-(pyridin-4-yl)quinolin-4-yl]carbonyl}amino)-3-fluorobenzoate

To a suspension of 500 mg (1.46 mmol) of the compound from example 31Ain 50 ml of dichloromethane were added a few drops of DMF and then 0.57ml (6.56 mmol) of oxalyl chloride. After stirring at RT for 15 min, thesolvent was removed, and the residue was taken up in 15 ml of pyridine.Subsequently, 321 mg (1.75 mmol) of ethyl 4-amino-3-fluorobenzoate wereadded, and the mixture was stirred at 80° C. overnight. After cooling toRT, the solvent was removed under reduced pressure and the residue wastaken up in 25 ml of dichloromethane. The solution was washed withwater, dried over sodium sulfate, filtered and concentrated. The residuewas purified by means of column chromatography (silica gel, eluent:dichloromethane/methanol 97:3). 90 mg (12% of theory) of the titlecompound were obtained, which were used directly in the subsequentstage.

Example 72A Methyl4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-[(methoxymethyl)sulfanyl]benzoate

The title compound was obtained as a by-product in the preparation ofthe compound from example 52A (for description see therein).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.78 (s, 1H), 8.25 (dd, 2H), 8.04(d, 1H), 7.95 (td, 2H), 7.83 (d, 1H), 7.66-7.61 (m, 2H), 7.60-7.51 (m,3H), 5.10 (s, 2H), 3.88 (s, 3H), 3.36 (s, 3H), 2.50 (s, 3H, hidden).

LC/MS (Method 21, ESIpos): R_(t)=1.40 min, m/z=551/553 [M+H]⁺.

Example 73A Methyl 4-amino-3-[(trifluoromethyl)sulfanyl]benzoate

To a mixture of 400 mg (1.10 mmol) of dimethyl3,3′-disulfanediylbis(4-aminobenzoate) [described in Org. Prep. Proc.Int. 2003, 35 (5), 520-524] in 10 ml of DMF were added 389 mg (3.29mmol) of sodium hydroxymethanesulfinate (Rongalit™), and the reactionmixture was stirred at RT for 15 min. Subsequently, 725 mg (2.20 mmol)of 3,3-dimethyl-1-(trifluoromethyl)-1,2-benzodioxole were added. Afterstirring at RT for 30 min, the mixture was purified directly by means ofpreparative HPLC (method 5). The combined product-containing fractionswere concentrated and dried under reduced pressure. The residue wastaken up in dichloromethane, the solution was concentrated again and theresidue was dried once again under reduced pressure. 185 mg (67% oftheory, 100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.94 (d, 1H), 7.77 (dd, 1H), 6.83 (d,1H), 6.71 (s, 2H), 3.77 (s, 3H).

LC/MS (Method 22, ESIpos): R_(t)=2.16 min, m/z=252 [M+H]⁺.

Example 74A Methyl 4-amino-3-[(trifluoromethyl)sulfonyl]benzoate

To a mixture of 200 mg (0.80 mmol) of the compound from example 73A in 5ml of acetonitrile were added, at 0° C., 3.3 mg (0.016 mmol) ofruthenium(III) chloride and 511 mg (2.39 mmol) of sodium periodate.Subsequently, 5 ml of water precooled to 0° C. were added, and themixture was stirred at 0° C. for 15 min and then at RT overnight.Thereafter, a further 3.3 mg (0.016 mmol) of ruthenium(III) chloride and511 mg (2.39 mmol) of sodium periodate were added, and the mixture wasstirred at RT for another 2 h. Then the mixture was admixed with ethylacetate and washed once with water. The aqueous phase was reextractedonce with ethyl acetate. The combined organic phases were washed oncewith saturated sodium chloride solution, dried over magnesium sulfate,filtered and concentrated. The residue was purified by means ofpreparative HPLC (method 18). The combined product-containing fractionswere concentrated and dried under reduced pressure. The residue wastaken up in dichloromethane, the solution was concentrated again and theresidue was dried once again under reduced pressure. 50 mg (21% oftheory, 96% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.11 (d, 1H), 7.98 (dd, 1H), 7.34(br. s, 2H), 7.03 (d, 1H), 3.81 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=0.94 min, m/z=284 [M+H]⁺.

Example 75A Methyl4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-[(trifluoromethyl)sulfonyl]benzoate

To a solution of 62 mg (0.16 mmol) of the compound from example 2A and45 mg (0.16 mmol) of the compound from example 74A in 0.65 ml of DMFunder argon was added 0.24 ml (0.24 mmol) of a 1 M solution of potassiumtert-butoxide in THF. The mixture was stirred at RT for 30 min.Subsequently, the mixture was diluted with 0.018 ml (0.24 mmol) of TFAand purified directly by means of preparative HPLC (method 18). 45 mg(46% of theory, 96% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.03 (s, 1H), 8.62 (dd, 1H), 8.57(s, 1H), 8.41 (d, 1H), 8.09-8.02 (m, 2H), 7.95 (dd, 1H), 7.67-7.60 (m,2H), 7.60-7.49 (m, 3H), 3.96 (s, 3H), 2.48 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.42 min, m/z=607/609 [M+H]+.

Example 76A Methyl4-{[(6-bromo-3-methyl-1-oxido-2-phenylquinolin-4-yl)carbonyl]amino}-3-[(trifluoromethyl)sulfanyl]benzoate

To a solution of 90 mg (0.16 mmol) of the compound from example 53A in 5ml of dichloromethane were added 58 mg (0.24 ml, 70% purity) of3-chloroperbenzoic acid, and the mixture was stirred at RT for 3 h.Subsequently, a further 39 mg (0.16 mmol, 70% purity) of3-chloroperbenzoic acid were added, and the mixture was stirred at RTfor another 2.5 h. Thereafter, a further 20 mg (0.08 mmol, 70% purity)of 3-chloroperbenzoic acid were added, and the mixture was stirred at RTfor yet another 1 h. Thereafter, the mixture was admixed with 5 ml ofsaturated aqueous sodium hydrogencarbonate solution and stirred for afew minutes, and then 1 ml of 10% sodium thiosulfate solution was added.After being left to stand at RT for about 80 h, the mixture was dilutedwith dichloromethane and water, the phases were separated, and then theaqueous phase was extracted once with dichloromethane. The combinedorganic phases were dried over magnesium sulfate, filtered andconcentrated. The residue was purified by means of preparative HPLC(method 5). Drying under reduced pressure gave 48 mg (52% of theory,purity 100%) of the title compound.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.28 (s, 1H), 8.52 (d, 1H), 8.34 (s,1H), 8.26 (dd, 1H), 8.22 (d, 1H), 8.01 (dd, 1H), 7.98 (d, 1H), 7.62-7.56(m, 2H), 7.56-7.50 (m, 1H), 7.44 (d, 2H), 3.92 (s, 3H), 2.19 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.21 min, m/z=591/593 [M+H]⁺.

Example 77A 6-Bromo-5-chloro-3-methyl-2-phenylquinoline-4-carboxylicacid

2.50 g (9.60 mmol) of 5-bromo-4-chloro-1H-indole-2,3-dione wereinitially charged in 21.6 ml of acetic acid, and 1.29 g (9.60 mmol) of1-phenylpropan-1-one were added. The reaction mixture was stirred at 75°C. for 5 min. Subsequently, 7.2 ml of concentrated hydrochloric acidwere added, and the mixture was stirred at 105° C. for 28 h. Aftercooling to RT, the reaction mixture was added to 100 ml of 1 Mhydrochloric acid, and the precipitated solids were filtered off. Thesolids were washed twice with water and suspended in ethyl acetate, andthe suspension was extracted three times with 75 ml of 1 M sodiumhydroxide solution. The combined sodium hydroxide solution phases werethen adjusted to pH 4 with concentrated hydrochloric acid. Theprecipitated solids were filtered off, washed twice with water and driedunder reduced pressure to obtain a first intermediate batch of thetarget compound. The ethyl acetate phase previously obtained wasextracted twice with 100 ml of water, and the two aqueous phases wereadjusted to pH 1 with concentrated hydrochloric acid and extracted twicewith 100 ml of ethyl acetate. The combined ethyl acetate phases weredried over sodium sulfate, filtered and concentrated. The residue wasdried to obtain a second intermediate batch of the target compound. Thetwo intermediate batches were then combined, taken up again in 100 ml of1 M sodium hydroxide solution and extracted twice with 50 ml of ethylacetate. The aqueous phase was adjusted to pH 4 with concentratedhydrochloric acid, and the solids formed were filtered off, washed twicewith 10 ml of water and dried under reduced pressure. In this way, 2.23g (53% of theory, 86% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=14.17 (br. s, 1H), 8.11 (d, 1H), 7.98(d, 1H), 7.66-7.59 (m, 2H), 7.58-7.50 (m, 3H), 2.39 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=0.97 min, m/z=376/378 [M+H]⁺.

Example 78A(6-Bromo-5-chloro-3-methyl-2-phenylquinolin-4-yl)(1H-imidazol-1-yl)methanone

To a solution of 2.20 g (5.02 mmol, 86% purity) of the compound fromexample 77A in 12 ml of DMF were added, at RT, 1.42 g (8.74 mmol) ofN,N′-carbonyldiimidazole, and the mixture was stirred at bathtemperature 120° C. for 6 h. Subsequently, a further 552 mg (3.40 mmol)of N,N′-carbonyldiimidazole were added, and the mixture was stirred atbath temperature 120° C. for another 4 h. Thereafter, another 552 mg(3.40 mmol) of N,N′-carbonyldiimidazole were added, and the mixture wasstirred at bath temperature 140° C. for a further 5 h. Thereafter, 100ml each of water and ethyl acetate were added to the mixture, the phaseswere separated and then the aqueous phase was extracted once with ethylacetate. The combined organic phases were washed once with saturatedsodium chloride solution, dried over sodium sulfate, filtered andconcentrated. The residue was taken up in dichloromethane and purifiedby means of column chromatography (100 g of silica gel, eluent:cyclohexane/ethyl acetate 7:3, Biotage). 362 mg (17% of theory, 100%purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.5-7.5 (br. m, 2H), 8.18 (d, 1H),8.09 (d, 1H), 7.71-7.66 (m, 2H), 7.59-7.49 (m, 3H), 7.27 (br. s, 1H),2.25 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.25 min, m/z=426/428 [M+H]⁺.

Example 79A Methyl4-{[(6-bromo-5-chloro-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoate

To a solution of 357 mg (0.84 mmol) of the compound from example 78A and156 mg (0.92 mmol) of methyl 4-amino-3-fluorobenzoate in 1.0 ml of DMFunder argon was added 0.84 ml (0.84 mmol) of a 1 M solution of potassiumtert-butoxide in THF. The mixture was stirred at RT for 2.5 h.Subsequently, another 0.84 ml (0.84 mmol) of a 1 M solution of potassiumtert-butoxide in THF was added, and stirring of the mixture wascontinued at RT overnight. Thereafter, the mixture was admixed with 30ml of 10% aqueous citric acid solution and 30 ml of water. Theprecipitate formed was filtered off, washed twice with 10 ml of waterand dried under reduced pressure. 289 mg of a product batch wereobtained, in which the title compound, by LC/MS analysis, was present in4% purity (3% of theory). This material was used in subsequent reactionswithout further purification.

LC/MS (Method 23, ESIpos): R_(t)=4.16 min, m/z=527/529 [M+H]⁺.

Example 80A Methyl4-[({6-bromo-3-[bromo(difluoro)methyl]-2-phenylquinolin-4-yl}carbonyl)amino]-3-fluorobenzoate

To a mixture of 133 mg (0.25 mmol) of the compound from example 64A in 4ml of tetrachloromethane were added 103 mg (0.58 mmol) ofN-bromosuccinimide and 2.1 mg (0.013 mmol) of2,2′-azobis-2-methylpropanenitrile. The mixture was irradiated with a UVlamp at 300 W for 24 h, in the course of which the internal temperaturerose to 80°-90° C. After this period, another 103 mg (0.58 mmol) ofN-bromosuccinimide and 2.1 mg (0.013 mmol) of2,2′-azobis-2-methylpropanenitrile were added, and the mixture wasirradiated with a UV lamp at 300 W and an internal temperature of80°−90° C. for a further 48 h. Subsequently, yet another 103 mg (0.58mmol) of N-bromosuccinimide and 2.1 mg (0.013 mmol) of2,2′-azobis-2-methylpropanenitrile were added, and the mixture wasirradiated with a UV lamp at 300 W and an internal temperature of80°-90° C. for another 24 h. Thereafter, the solvent was removed and theresidue was purified by means of preparative HPLC (method 20). 35 mg(18% of theory, 76% purity) of the title compound were obtained.

LC/MS (Method 1, ESIpos): R_(t)=1.31 min, m/z=607/609/611 [M+H]⁺.

Example 81A Methyl4-({[6-bromo-2-phenyl-3-(trifluoromethyl)quinolin-4-yl]carbonyl}amino)-3-fluorobenzoate

To a solution of 32 mg (0.04 mmol, 76% purity) of the compound fromexample 80A in 1.6 ml of acetonitrile under argon were added 27 mg (0.21mmol) of silver(I) fluoride, and the mixture was stirred at 80° C. for30 min. After cooling to RT, the solid constituents were filtered off,and the filtrate was purified by means of preparative HPLC (method 19).4.5 mg (18% of theory, 90% purity) of the title compound were obtained.

LC/MS (Method 23, ESIpos): R_(t)=4.22 min, m/z=547/549 [M+H]⁺.

Example 82A Methyl4-{[(6-chloro-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoate

To a solution of 210 mg (0.71 mmol) of6-chloro-3-methyl-2-phenylquinoline-4-carboxylic acid in 5 ml of DMFwere added, at RT, 239 mg (1.41 mmol) of methyl4-amino-3-fluorobenzoate, 402 mg (1.06 mmol) of HATU and 182 mg (1.41mmol) of N,N-diisopropylethylamine. The mixture was stirred at 60° C.for 1 h. After cooling to RT, the mixture was introduced into 10%aqueous citric acid solution, and the precipitate formed was filteredoff, washed three times with water and dried under reduced pressure. Thematerial thus obtained was suspended in 4.5 ml of DMF, 117 mg (0.69mmol) of methyl 4-amino-3-fluorobenzoate and 0.94 ml (0.94 mmol) of a 1M solution of potassium tert-butoxide in THF were added to thesuspension at RT, and the mixture was stirred at RT for 30 min.Thereafter, the mixture was introduced into 30 ml of 10% aqueous citricacid solution, and extracted twice with ethyl acetate. The combinedorganic phases were dried over sodium sulfate, filtered andconcentrated. The residue was taken up in a mixture of DMSO, water andacetonitrile and, after some suspended material had been filtered off,purified by means of preparative HPLC (method 19). The combinedproduct-containing fractions were concentrated down to a residual volumeof aqueous phase, and the aqueous residue was extracted twice with ethylacetate. The combined ethyl acetate phases were dried over sodiumsulfate, filtered and concentrated. The residue was dried under reducedpressure. 78 mg (25% of theory, 100% purity) of the title compound wereobtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.10 (s, 1H), 8.28 (t, 1H),8.15-8.07 (m, 1H), 7.91 (d, 1H), 7.88-7.79 (m, 3H), 7.66-7.60 (m, 2H),7.60-7.49 (m, 3H), 3.89 (s, 3H), 2.43 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.19 min, m/z=449 [M+H]⁺.

Example 83A Methyl4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-[(methoxymethyl)sulfonyl]benzoate

To a solution of 134 mg (0.24 mmol) of the compound from example 72A in3.5 ml of dichloromethane were added 120 mg (0.49 mmol, 70% purity) of3-chloroperbenzoic acid. The mixture was stirred at RT for 15 min.Subsequently, the mixture was diluted with dichloromethane and washedwith saturated sodium hydrogencarbonate solution. The aqueous phase wasreextracted once with dichloromethane, and the combined organic phaseswere dried over magnesium sulfate, filtered and concentrated. Theresidue was purified by means of preparative HPLC (method 18). Dryingunder reduced pressure gave 77 mg (54% of theory, purity 100%) of thetitle compound.

LC/MS (Method 1, ESIpos): R_(t)=1.24 min, m/z=583/585 [M+H]⁺.

¹H-NMR (500 MHz, DMSO-d₆): δ [ppm]=10.63 (s, 1H), 8.51-8.46 (m, 2H),8.43 (dd, 1H), 8.20 (d, 1H), 8.05 (d, 1H), 7.95 (dd, 1H), 7.67-7.62 (m,2H), 7.59-7.49 (m, 3H), 5.03 (s, 2H), 3.94 (s, 3H), 3.41 (s, 3H).

Example 84A 6-tert-Butyl-3-methyl-2-phenylquinoline-4-carboxylic acid

5.00 g (24.60 mmol) of 5-tert-butyl-1H-indole-2,3-dione were initiallycharged in 50 ml of acetic acid, and 3.30 g (24.60 mmol) of1-phenylpropan-1-one were added. The reaction mixture was stirred at 75°C. for 5 min. Subsequently, 18 ml of concentrated hydrochloric acid wereadded, and the mixture was stirred at 105° C. overnight. After coolingto RT, the reaction mixture was added to 1 liter of 1 M hydrochloricacid and the precipitated solids were filtered off. The solids werewashed with water, dried under air and then stirred with 50 ml ofacetonitrile. The solids were filtered off again and dried under air andfinally under reduced pressure. 4.85 g (61% of theory, 99% purity) ofthe title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=14.09 (br. s, 1H), 7.99 (d, 1H), 7.92(dd, 1H), 7.66 (d, 1H), 7.62-7.57 (m, 2H), 7.55-7.45 (m, 3H), 2.37 (s,3H), 1.39 (s, 9H).

LC/MS (Method 1, ESIpos): R_(t)=0.69 min, m/z=320 [M+H]⁺.

Example 85A Methyl4-{[(6-tert-butyl-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoate

To a solution of 200 mg (0.63 mmol) of the compound from example 84A and127 mg (0.75 mmol) of methyl 4-amino-3-fluorobenzoate in 5.0 ml of DMFunder argon were added 357 mg (0.94 mmol) of HATU and 162 mg (1.25 mmol)of N,N-diisopropylethylamine. The mixture was stirred at 60° C.overnight. Subsequently, another 127 mg (0.51 mmol) of methyl4-amino-3-fluorobenzoate were added, and the mixture was stirred at 60°C. for a further 7.5 h and then left to stand at RT for about 80 h.Thereafter, 0.94 ml (0.94 mmol) of a 1 M solution of potassiumtert-butoxide in THF was added, and the mixture was stirred for a whileand then left to stand at RT for a further night. Another 0.94 ml (0.94mmol) of a 1 M solution of potassium tert-butoxide in THF was added, andthe mixture was first stirred at RT for 8 h and then left to stand at RTfor a further night. Thereafter, the mixture was introduced into about40 ml of 5% aqueous citric acid solution, and extracted twice with ethylacetate. The combined organic phases were washed once with saturatedsodium chloride solution, dried over magnesium sulfate, filtered andconcentrated. The residue was purified by means of preparative HPLC(method 18). The combined product-containing fractions wereconcentrated, and the residue was taken up in dichloromethane,concentrated again and then dried under reduced pressure. 86 mg (28% oftheory, 98% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.07 (s, 1H), 8.10 (t, 1H), 8.05 (d,1H), 7.96 (dd, 1H), 7.92 (dd, 1H), 7.87 (dd, 1H), 7.77 (d, 1H),7.65-7.60 (m, 2H), 7.59-7.49 (m, 3H), 3.89 (s, 3H), 2.42 (s, 3H), 1.38(s, 9H).

LC/MS (Method 1, ESIpos): R_(t)=1.28 min, m/z=471 [M+H]⁺.

Example 86A tert-Butyl[2-nitro-5-(pentafluoro-λ⁶-sulfanyl)phenyl]acetate

24.90 g (99.94 mmol) of 1-nitro-4-(pentafluoro-λ⁶-sulfanyl)benzene wereinitially charged in 200 ml of anhydrous DMF under argon. The solutionwas cooled to −30° C., and 15.05 g (14.30 ml, 99.94 mmol) of tert-butylchloroacetate were added. Then a solution of 44.86 g (339.74 mmol) ofpotassium tert-butoxide in 400 ml of anhydrous DMF was slowly addeddropwise. A deep blue solution formed. The reaction mixture was stirredovernight, in the course of which it warmed up gradually to roomtemperature. Thereafter, the reaction solution was added cautiously to atert-butyl methyl ether/water mixture while stirring. The phases wereseparated, and the organic phase was washed once with water and driedover sodium sulfate. The solvent was removed, and the residue waspurified by column chromatography (silica gel, eluent: cyclohexane/ethylacetate 20:1). After the solvent had been removed, the residue wasstirred in pentane. The solids were filtered off and dried under reducedpressure. 13.67 g (38% of theory, >99% purity) of the title compoundwere obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.28 (d, 1H), 8.26 (d, 1H), 8.14 (dd,1H), 4.12 (s, 2H), 1.39 (s, 9H).

LC/MS (Method 22, ESIneg): R_(t)=2.64 min, m/z=362 [M−H]−.

Example 87A tert-Butyl[2-amino-5-(pentafluoro-λ⁶-sulfanyl)phenyl]acetate

13.67 g (37.63 mmol) of the compound from example 86A were initiallycharged together with 1.98 g (1.88 mmol) of palladium on activatedcarbon (10%) in 500 ml of ethanol. The reaction mixture was hydrogenatedat RT under standard pressure for 3 h. After the reaction had ended, thepalladium catalyst was filtered off through Celite and the filtrate wasconcentrated. The residue was stirred with a pentane/tert-butyl methylether mixture, and the solids were filtered off and dried under reducedpressure. 10 g (80% of theory, >99% purity) of the title compound wereobtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.49-7.36 (m, 2H), 6.68 (d, 1H), 5.75(s, 2H), 3.50 (s, 2H), 1.40 (s, 9H).

LC/MS (Method 22, ESIpos): R_(t)=2.53 min, m/z=278 [M−C₄H₈+H]⁺.

Example 88A3-Methyl-6-(pentafluoro-λ⁶-sulfanyl)-2-phenylquinoline-4-carboxylic Acid

4.79 g (14.38 mmol) of the compound from example 87A were initiallycharged in 71.4 ml of acetic acid. 2.13 g (1.94 ml, 14.38 mmol) of1-phenylpropane-1,2-dione were added, and the reaction mixture wasstirred at 75° C. for 5 min. Then 23.8 ml of conc. hydrochloric acidwere added, and stirring of the mixture was continued at 105° C.overnight. The reaction mixture was then added cautiously to an ethylacetate/water mixture while stirring. The phases were separated, and theaqueous phase was extracted three times with ethyl acetate. The combinedorganic phases were dried over sodium sulfate and the solvent wasremoved. The residue was stirred with a pentane/tert-butyl methyl ethermixture. The solids were filtered off and then purified by means ofcolumn chromatography (silica gel, eluent: ethyl acetate/methanol 10:1).After the solvent had been removed, the solids were dried under reducedpressure. 980 mg (17% of theory, 99% purity) of the title compound wereobtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=15.02 (br. s, 1H), 8.31 (d, 1H),8.26-8.14 (m, 2H), 7.67-7.58 (m, 2H), 7.58-7.48 (m, 3H), 2.40 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.00 min, m/z=390 [M+H]+.

Example 89A1H-Imidazol-1-yl[3-methyl-6-(pentafluoro-λ⁶-sulfanyl)-2-phenylquinolin-4-yl]methanone

838 mg (2.15 mmol) of the compound from example 88A were dissolved in 5ml of DMF, and 698 mg (4.30 mmol) of N,N′-carbonyldiimidazole were addedat RT. The reaction mixture was stirred at 60° C. overnight. Thereafter,a further 174 mg (1.08 mmol) of N,N′-carbonyldiimidazole were added, andthe mixture was stirred at 60° C. for a further hour. Another 349 mg(2.15 mmol) of N,N′-carbonyldiimidazole were added and the mixture wasstirred at 60° C. for another 3 h. The reaction mixture was then admixedwith water and tert-butyl methyl ether. The phases were separated, andthe aqueous phase was extracted three times with tert-butyl methylether. The combined organic phases were dried over sodium sulfate. Afterthe solvent had been removed, the residue was dried under reducedpressure overnight. 520 mg (52% of theory, 95% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.90-7.37 (br. m, 2H), 8.36 (d, 1H),8.28 (dd, 1H), 8.04 (br. s, 1H), 7.78-7.67 (m, 2H), 7.63-7.49 (m, 3H),7.23 (br. s, 1H), 2.28 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.18 min, m/z=440 [M+H]⁺.

Example 90A Methyl3-fluoro-4-({[3-methyl-6-(pentafluoro-λ⁶-sulfanyl)-2-phenylquinolin-4-yl]carbonyl}amino)benzoate

100 mg (0.23 mmol) of the compound from example 89A and 39 mg (0.23mmol) of methyl 4-amino-3-fluorobenzoate were dissolved in 2 ml of DMF.0.57 ml (0.57 mmol) of a 1 M solution of potassium tert-butoxide in THFwas added, and stirring of the mixture was continued at RT for 1 h. Thiswas followed by addition of ethyl acetate and water. The phases wereseparated, and the aqueous phase was extracted three times with ethylacetate. The combined organic phases were washed with water, dried oversodium sulfate, filtered and concentrated. The residue was stirred in apentane/tert-butyl methyl ether mixture. The solids were filtered offand dried under reduced pressure. 117 mg (87% of theory, 91% purity) ofthe title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.17 (s, 1H), 8.35-8.22 (m, 3H),8.15 (t, 1H), 7.96-7.84 (m, 2H), 7.71-7.63 (m, 2H), 7.63-7.44 (m, 3H),3.89 (s, 3H), 2.48 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.33 min, m/z=541 [M+H]+.

Example 91A Methyl 6-iodo-3-methyl-2-phenylquinoline-4-carboxylate

22.4 g (57.5 mmol) of the compound from example 5A were initiallycharged together with 28.1 g (86.23 mmol) of cesium carbonate in 224 mlof acetonitrile under argon. 3.6 ml (57.5 mmol) of iodomethane wereadded at RT. The reaction mixture was heated to 40° C. and stirred for 1h. Subsequently, a further 3.6 ml (57.5 mmol) of iodomethane were added,and the mixture was stirred at 40° C. for another 2 h. The reactionmixture was then cooled to RT, and ethyl acetate and water were added.The phases were separated, and the organic phase was washed once withsaturated sodium carbonate solution. A precipitate was formed, which wasfiltered off through kieselguhr. The filtrate was dried over sodiumsulfate, filtered and concentrated. The residue was purified by means ofcolumn chromatography (silica gel, eluent cyclohexane/ethyl acetate10:1). Drying under reduced pressure gave 12.7 g (55% of theory, 96%purity) of the title compound.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.12 (d, 1H), 8.06 (dd, 1H), 7.84 (d,1H), 7.64-7.59 (m, 2H), 7.57-7.47 (m, 3H), 4.07 (s, 3H), 2.35 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.26 min, m/z=404 [M+H]⁺.

Example 92A Methyl 6-formyl-3-methyl-2-phenylquinoline-4-carboxylate

5.0 g (12.4 mmol) of the compound from example 91A were dissolved in 98ml of anhydrous THF under argon, and the mixture was cooled to −50° C.This was followed by successive dropwise addition of 35.4 ml (37.2 mmol)of a 1.05 M solution of isopropylmagnesium chloride/lithium chloridecomplex in THF and 3.2 ml (37.2 mmol) of 1,4-dioxane. The reactionmixture was stirred at −50° C. for 1 h and then cooled to −78° C. Then9.5 ml (124 mmol) of absolute DMF were added dropwise. The reactionmixture was allowed to come to RT while stirring overnight, and thenethyl acetate and water were added. The phases were separated, and theorganic phase was washed once with water, dried over sodium sulfate,filtered and concentrated. In the attempt to purify the residue by meansof column chromatography (silica gel, eluent: cyclohexane/ethyl acetate6:1), the product precipitated out on the column. The chromatographicpurification was then stopped and the silica gel was stirred with ethylacetate. After filtration, the filtrate was concentrated. The residuewas stirred in methanol, and the solids were filtered off and driedunder reduced pressure. 2.29 g (59% of theory, 98% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.24 (s, 1H), 8.44 (d, 1H),8.24-8.12 (m, 2H), 7.71-7.60 (m, 2H), 7.59-7.47 (m, 3H), 4.12 (s, 3H),2.40 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.06 min, m/z=306 [M+H]⁺.

Example 93A Methyl6-(difluoromethyl)-3-methyl-2-phenylquinoline-4-carboxylate

1.0 g (3.2 mmol) of the compound from example 92A were dissolved in 40ml of dichloromethane. The mixture was cooled down to −78° C., and 1.4 g(7.86 mmol, 90% purity) of N-ethyl-N-(trifluoro-λ⁴-sulfanyl)ethanamine(DAST) was added gradually. The reaction mixture was stirred overnight,in the course of which it warmed up to RT, and then saturated aqueoussodium hydrogencarbonate solution was added. The phases were separated,and the aqueous phase was extracted three times with ethyl acetate. Thecombined organic phases were dried over sodium sulfate, filtered andconcentrated. The residue was purified by means of column chromatography(silica gel, eluent cyclohexane/ethyl acetate 5:1). After the solventhad been removed, the residue was dried under reduced pressure. 737 mg(69% of theory, >99% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.21 (d, 1H), 8.02 (br. s, 1H), 7.95(d, 1H), 7.69-7.61 (m, 2H), 7.59-7.48 (m, 3H), 7.28 (t, 1H), 4.09 (s,3H), 2.38 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.15 min, m/z=328 [M+H]⁺.

Example 94A 6-(Difluoromethyl)-3-methyl-2-phenylquinoline-4-carboxylicacid

100 mg (0.31 mmol) of the compound from example 93A were dissolved in 5ml of a THF/methanol mixture (5:1), and 1.53 ml (1.53 mmol) of a 1 Msolution of lithium hydroxide in water were added. The reaction mixturewas stirred at 50° C. for 7 h and then cooled to RT, and ethyl acetateand water were added. The phases were separated, and the aqueous phasewas adjusted to pH 1-2 with 1 M hydrochloric acid and extracted threetimes with ethyl acetate. The combined organic extracts were dried oversodium sulfate, filtered and concentrated. The residue was stirred in apentane/tert-butyl methyl ether mixture, and the solids were filteredoff and dried under reduced pressure. 61 mg (96% of theory, 99% purity)of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=14.37 (br. s, 1H), 8.20 (d, 1H), 8.02(d, 1H), 7.92 (dd, 1H), 7.67-7.61 (m, 2H), 7.59-7.49 (m, 3H), 7.33 (t,1H), 2.42 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=0.72 min, m/z=314 [M+H]⁺.

Example 95A Methyl4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2,3-difluorobenzoate

150 mg (0.38 mmol) of the compound from example 2A and 72 mg (0.38 mmol)of methyl 4-amino-2,3-difluorobenzoate were dissolved in 3.4 ml of DMF.0.96 ml (0.96 mmol) of a 1 M solution of potassium tert-butoxide in THFwas added, and stirring of the mixture was continued at RT for 1 h. Thiswas followed by addition of ethyl acetate and water. The phases wereseparated, and the aqueous phase was extracted three times with ethylacetate. The combined organic phases were washed with water and driedover sodium sulfate, and the solvent was removed on a rotary evaporator.The residue was dried under reduced pressure. 110 mg (50% of theory, 89%purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.29 (s, 1H), 8.12-8.00 (m, 2H),7.98 (d, 1H), 7.93 (dd, 1H), 7.87-7.77 (m, 1H), 7.66-7.60 (m, 2H),7.60-7.48 (m, 3H), 3.90 (s, 3H), 2.43 (s, 3H).

LC/MS (Method 23, ESIpos): R_(t)=4.00 min, m/z=511/513 [M+H]⁺.

Example 96A Methyl4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2,5-difluorobenzoate

150 mg (0.38 mmol) of the compound from example 2A and 72 mg (0.38 mmol)of methyl 4-amino-2,5-difluorobenzoate were dissolved in 3.4 ml of DMF.0.96 ml (0.96 mmol) of a 1 M solution of potassium tert-butoxide in THFwas added, and stirring of the mixture was continued at RT for 1 h. Thiswas followed by addition of ethyl acetate and water. The phases wereseparated, and the aqueous phase was extracted three times with ethylacetate. The combined organic phases were washed with water and driedover sodium sulfate, and the solvent was removed. The residue waspurified by means of column chromatography (25 g of silica gel, eluent:cyclohexane/ethyl acetate 4:1, Biotage Isolera™ One). After the solventhad been removed, the residue was dried under reduced pressure. 102 mg(44% of theory, 85% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.27 (s, 1H), 8.31 (dd, 1H), 8.04(d, 1H), 8.01 (d, 1H), 7.93 (dd, 1H), 7.81 (dd, 1H), 7.65-7.59 (m, 2H),7.59-7.49 (m, 3H), 3.88 (s, 3H), 2.41 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.23 min, m/z=511/513 [M+H]⁺.

Example 97A 6-Bromo-3-fluoro-2-phenylquinoline-4-carboxylic acid

1.75 g (6.97 mmol, 90% purity) of 5-bromo-1H-indole-2,3-dione wereinitially charged in 15 ml of acetic acid, and 0.96 g (6.97 mmol) of2-fluoro-1-phenylethanone was added. The reaction mixture was stirred at75° C. for 5 min. Subsequently, 5 ml of conc. hydrochloric acid wereadded, and stirring of the mixture was continued at 115° C. overnight.After cooling to RT, the reaction mixture was added to 100 ml of 1 Mhydrochloric acid. The precipitated solids were filtered off, washedtwice with 10 ml of water and dried under reduced pressure. The residuewas purified by means of preparative HPLC (method 18). 501 mg (20% oftheory, 98% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=14.66 (br. s, 1H), 8.21 (d, 1H), 8.11(d, 1H), 8.04-7.96 (m, 3H), 7.62-7.56 (m, 3H).

LC/MS (Method 1, ESIpos): R_(t)=0.98 min, m/z=346/348 [M+H]⁺.

Example 98A Methyl4-{[(6-bromo-3-fluoro-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoate

To a solution of 200 mg (0.58 mmol) of the compound from example 97A in4.1 ml of DMF were added, at RT, 195 mg (1.16 mmol) of methyl4-amino-3-fluorobenzoate, 330 mg (0.87 mmol) of HATU and 149 mg (1.16mmol) of N,N-diisopropylethylamine. The mixture was first stirred at 60°C. for 4.5 h and then left to stand at RT for two days. Thereafter, themixture was introduced into aqueous 10% aqueous citric acid solution,and extracted twice with 30 ml of ethyl acetate. The combined organicphases were washed once with 60 ml of saturated sodium chloridesolution, dried over sodium sulfate and concentrated. The residue wastaken up in 3 ml of DMSO and 3 ml of acetonitrile, and purified by meansof preparative HPLC (Method 18). 51 mg (16% of theory, 91% purity) ofthe title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=11.25 (s, 1H), 8.39 (t, 1H), 8.17-8.12(m, 2H), 8.09-8.03 (m, 2H), 8.00 (dd, 1H), 7.92 (dd, 1H), 7.85 (dd, 1H),7.65-7.57 (m, 3H), 3.89 (s, 3H).

LC/MS (Method 23, ESIpos): R_(t)=4.30 min, m/z=497/499 [M+H]⁺.

Example 99A 3-Chloro-6-iodo-2-phenylquinoline-4-carboxylic acid

10.00 g (36.63 mmol) of 5-iodo-1H-indole-2,3-dione were initiallycharged in 100 ml of acetic acid, and 5.66 g (36.63 mmol) of2-chloro-1-phenylethanone were added. The reaction mixture was stirredat 75° C. for 5 min. Subsequently, 5 ml of conc. hydrochloric acid wereadded, and stirring of the mixture was continued at 105° C. overnight.After cooling to RT, the reaction mixture was added to 200 ml of 1 Mhydrochloric acid. The precipitated solids were filtered off, washedtwice with water and dried under reduced pressure. The solids were thenstirred in 50 ml of acetonitrile, filtered off again and dried againunder reduced pressure. 4.45 g (16% of theory, 54% purity) of the titlecompound were obtained.

LC/MS (Method 1, ESIpos): R_(t)=0.94 min, m/z=409 [M+H]⁺.

Example 100A(3-Chloro-6-iodo-2-phenylquinolin-4-yl)(1H-imidazol-1-yl)methanone

To a solution of 700 mg (0.92 mmol, 54% purity) of the compound fromexample 99A in 6 ml of DMF were added, at RT, 165 mg (1.02 mmol) ofN,N′-carbonyldiimidazole, and the mixture was stirred at 60° C. for 2 h.Subsequently, a further 165 mg (1.02 mmol) of N,N′-carbonyldiimidazolewere added, and the mixture was stirred at 60° C. for another 4 h. Aftercooling to RT, the mixture was introduced into 50 ml of water whilestirring. The solids formed were filtered off, washed twice with 2 mleach time of water and dried under reduced pressure. 699 mg (“>100%” oftheory, still containing solvent, 81% purity by LC/MS) of the titlecompound were obtained.

LC/MS (Method 1, ESIpos): R_(t)=1.17 min, m/z=460 [M+H]⁺.

Example 101A Methyl4-{[(3-chloro-6-iodo-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoate

To a solution of 110 mg (0.23 mmol) of the compound from example 100Aand 61 mg (0.36 mmol) of methyl 4-amino-3-fluorobenzoate in 2 ml of DMFwas added 0.36 ml (0.36 mmol) of a 1 M solution of potassiumtert-butoxide in THF, and the mixture was stirred at RT for 1 h.Subsequently, the mixture was purified directly by means of preparativeHPLC (method 24). 46 mg (31% of theory, 90% purity) of the titlecompound were obtained.

LC/MS (Method 23, ESIpos): R_(t)=4.26 min, m/z=561 [M+H]⁺.

Example 102A 6-Bromo-3-chloro-2-phenylquinoline-4-carboxylic acid

10.00 g (44.24 mmol) of 5-bromo-1H-indole-2,3-dione were initiallycharged in 120 ml of acetic acid, and 6.84 g (44.24 mmol) of2-chloro-1-phenylethanone were added. The reaction mixture was stirredat 75° C. for 5 min. Subsequently, 5 ml of conc. hydrochloric acid wereadded, and stirring of the mixture was continued at 105° C. overnight.After cooling to RT, the reaction mixture was added to 200 ml of 1 Mhydrochloric acid. The precipitated solids were filtered off, washedtwice with water and dried under reduced pressure. The solids were thenstirred in 50 ml of acetonitrile, filtered off again and dried againunder reduced pressure. 5.60 g (29% of theory, 82% purity) of the titlecompound were obtained.

LC/MS (Method 1, ESIpos): R_(t)=0.88 min, m/z=362/364 [M+H]⁺.

Example 103A(6-Bromo-3-chloro-2-phenylquinolin-4-yl)(1H-imidazol-1-yl)methanone

To a solution of 500 mg (1.13 mmol, 82% purity) of the compound fromexample 102A in 5 ml of DMF were added, at RT, 202 mg (1.24 mmol) ofN,N′-carbonyldiimidazole, and the mixture was stirred at 60° C. for 2 h.Subsequently, a further 202 mg (1.24 mmol) of N,N′-carbonyldiimidazolewere added, and the mixture was stirred at 60° C. for another 4 h. Aftercooling to RT, the mixture was admixed with 50 ml of aqueous citric acidsolution. The solids formed were filtered off, washed twice with 2 mleach time of water and dried under reduced pressure. 553 mg (95% oftheory, 80% purity) of the title compound were obtained.

LC/MS (Method 1, ESIpos): R_(t)=1.14 min, m/z=412/414 [M+H]⁺.

Example 104A Methyl4-{[(6-bromo-3-chloro-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoate

To a mixture of 80 mg (0.19 mmol) of the compound from example 103A and49 mg (0.29 mmol) of methyl 4-amino-3-fluorobenzoate in 2 ml of DMF wasadded 0.29 ml (0.29 mmol) of a 1 M solution of potassium tert-butoxidein THF, and the mixture was stirred at RT for 1 h. Subsequently, themixture was purified directly by means of preparative HPLC (method 24).45 mg (38% of theory, 85% purity) of the title compound were obtained.

LC/MS (Method 23, ESIpos): R_(t)=4.19 min, m/z=513/515 [M+H]⁺.

Example 105A 6-Bromo-3-cyclopropyl-2-phenylquinoline-4-carboxylic acid

Method A:

1.75 g (6.97 mmol, 90% purity) of 5-bromo-1H-indole-2,3-dione wereinitially charged in 15 ml of acetic acid, and 1.12 g (6.97 mmol) of2-cyclopropyl-1-phenylethanone was added [preparation described in WO2009/143049-A1, p. 182, Compound 99A]. The reaction mixture was stirredat 75° C. for 5 min. Subsequently, 5 ml of conc. hydrochloric acid wereadded, and stirring of the mixture was continued at 110° C. for 2.5 hand then at RT overnight. The reaction mixture was then added to 100 mlof 1 M hydrochloric acid. The precipitated solids were filtered off,washed twice with 10 ml of water and dried under reduced pressure. 2.23g of a crude product were obtained. 200 mg of this crude product werepurified by preparative HPLC (Method 4). This was used to obtain 43 mg(1.5% of theory based on 6.97 mmol of reactant, 93% purity) of the titlecompound.

Method B:

To a solution of 2.03 g (8.12 mmol, 90% purity) of5-bromo-1H-indole-2,3-dione in 20 ml of ethanol were added, at RT, 1.95g (12.18 mmol) of 2-cyclopropyl-1-phenylethanone [preparation describedin WO 2009/143049-A1, p. 182, Compound 99A] and 2.05 g (36.56 mmol) ofpotassium hydroxide. The reaction mixture was stirred at bathtemperature 100° C. for 1 h. After cooling to RT, the mixture wasadmixed with 300 ml of water and adjusted to pH 2 with conc.hydrochloric acid. The mixture was extracted twice with 20 ml each timeof ethyl acetate. The combined organic phases were dried over sodiumsulfate, filtered and concentrated. The residue was suspended in amixture of 30 ml of DMSO and 10 ml of acetonitrile, and the remainingsolids were filtered off and dried under reduced pressure. In this way,107 mg (4% of theory, purity 100%) of a first batch of the titlecompound were obtained. The filtrate was concentrated, and the residuewas purified by means of preparative HPLC (method 3), which gave 750 mg(25% of theory, 100% purity) of a second batch of the title compound.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=14.22 (br. s, 1H), 8.01 (d, 1H), 7.97(d, 1H), 7.93 (dd, 1H), 7.76-7.71 (m, 2H), 7.54-7.46 (m, 3H), 2.38-2.28(m, 1H), 0.76-0.66 (m, 2H), 0.33-0.25 (m, 2H).

LC/MS (Method 1, ESIpos): R_(t)=0.91 min, m/z=368/370 [M+H]⁺.

Example 106A Methyl4-{[(6-bromo-3-cyclopropyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoate

To a solution of 400 mg (1.09 mmol) of the compound from example 105A in6 ml of DMF were added, at RT, 367 mg (2.17 mmol) of methyl4-amino-3-fluorobenzoate, 620 mg (1.63 mmol) of HATU and 281 mg (2.17mmol) of N,N-diisopropylethylamine. The mixture was stirred at 60° C.for 5 h. Thereafter, a further 140 mg (1.09 mmol) ofN,N-diisopropylethylamine were added, and the mixture was stirred at 60°C. for another 2 h. After cooling to RT, 2.17 ml (2.17 mmol) of a 1 Msolution of potassium tert-butoxide in THF were added, and stirring ofthe mixture was continued at RT for 18 h. Subsequently, another 2.17 ml(2.17 mmol) of a 1 M solution of potassium tert-butoxide in THF wereadded, and stirring of the mixture was continued at RT for another 2 h.Thereafter, the mixture was introduced into 80 ml of a 10% aqueouscitric acid solution, and extracted twice with 50 ml each time of ethylacetate. The combined organic phases were dried over sodium sulfate,filtered and concentrated. The residue was taken up in a mixture of DMSOand water, and purified by means of preparative HPLC (method 18). 3.4 mg(0.6% of theory, 100% purity) of a first batch of the title compound and33 mg (5% of theory, 77% purity) of a second batch of the title compoundwere obtained.

¹H-NMR (500 MHz, DMSO-d₆): [ppm]=11.04 (s, 1H), 8.31 (t, 1H), 8.07-8.03(m, 2H), 7.96-7.91 (m, 2H), 7.86 (dd, 1H), 7.76 (dd, 2H), 7.56-7.48 (m,3H), 3.90 (s, 3H), 2.43-2.32 (m, 1H), 0.68 (d, 2H), 0.32 (d, 2H).

LC/MS (Method 1, ESIpos): R_(t)=1.31 min, m/z=519/521 [M+H]⁺.

Example 107A 6-Bromo-3,8-dimethyl-2-phenylquinoline-4-carboxylic acid

3.00 g (12.50 mmol) of 5-bromo-7-methyl-1H-indole-2,3-dione wereinitially charged in 34 ml of acetic acid, and 1.68 g (12.50 mmol) of1-phenylpropan-1-one were added. The reaction mixture was stirred at 75°C. for 5 min. Subsequently, 11 ml of conc. hydrochloric acid were added,and stirring of the mixture was continued at 115° C. overnight. Aftercooling to RT, the reaction mixture was added to 200 ml of 1 Mhydrochloric acid. The precipitated solids were filtered off, washedtwice with 10 ml of water and dried under reduced pressure. 3.02 g (64%of theory, 94% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=14.31 (br. s, 1H), 7.83 (s, 1H),7.77-7.63 (m, 3H), 7.57-7.49 (m, 3H), 2.70 (s, 3H), 2.41 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.15 min, m/z=356/358 [M+H]⁺.

Example 108A Methyl4-{[(6-bromo-3,8-dimethyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoate

To a solution of 500 mg (1.32 mmol, 94% purity) of the compound fromexample 107A in 9 ml of DMF were added, at RT, 448 mg (2.65 mmol) ofmethyl 4-amino-3-fluorobenzoate, 755 mg (1.98 mmol) of HATU and 342 mg(2.65 mmol) of N,N-diisopropylethylamine. The mixture was stirred at 60°C. for 2 h. Thereafter, a further 171 mg (1.32 mmol) ofN,N-diisopropylethylamine were added, and the mixture was stirred at 60°C. for another 7 h. After cooling to RT, 2.65 ml (2.65 mmol) of a 1 Msolution of potassium tert-butoxide in THF were added, and stirring ofthe mixture was continued at RT for 2 h. Subsequently, another 2.65 ml(2.65 mmol) of a 1 M solution of potassium tert-butoxide in THF wereadded, and stirring of the mixture was continued at RT for two days.Thereafter, the mixture was introduced into 200 ml of a 10% aqueouscitric acid solution. The precipitate formed was filtered off and driedunder reduced pressure. 651 mg (78% of theory, 80% purity) of the titlecompound were obtained.

LC/MS (Method 1, ESIpos): R_(t)=1.35 min, m/z=507/509 [M+H]⁺.

WORKING EXAMPLES Example 14-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}benzoic acid

To 177 mg (0.36 mmol) of the compound from example 34A were added first4.5 ml of THF and then a solution of 13 mg (0.54 mmol) of lithiumhydroxide in 1.5 ml of water. The reaction mixture was stirred at RT foreight days and then adjusted to pH 1-2 with 2 M hydrochloric acid. Theprecipitated solids were filtered off, washed with water, and driedunder reduced pressure at 60° C. overnight. 109 mg (65% of theory, 100%purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=11.25 (s, 1H), 8.06 (d, 1H), 8.01-7.99(m, 2H), 7.95 (dd, 1H), 7.92-7.87 (m, 3H), 7.65-7.63 (m, 2H), 7.58-7.51(m, 3H), 2.41 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.08 min, m/z=461/463 [M+H]⁺.

Example 26-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}nicotinicacid imidazole salt

To 100 mg (0.26 mmol) of the compound from example 2A were successivelyadded 2 ml of THF, 47 mg (0.31 mmol) of methyl 6-aminonicotinate and 22mg (0.56 mmol) of sodium hydride (60% in mineral oil). The reactionmixture was stirred at RT overnight, and then it was purified, withoutfurther workup, by means of preparative HPLC (method 8). 15 mg (11% oftheory, 100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=12.54 (br. s, 1H), 11.65 (s, 1H), 8.85(d, 1H), 8.43 (d, 1H), 8.36 (dd, 1H), 8.03 (d, 1H), 7.93-7.90 (m, 2H),7.64-7.61 (m, 4H), 7.58-7.49 (m, 4H), 7.01 (s, 1H), 2.40 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.07 min, m/z=462/464 [M+H]⁺.

Example 35-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}pyrazine-2-carboxylicAcid

100 mg (0.26 mmol) of the compound from example 2A and 43 mg (0.26 mmol)of ethyl 5-aminopyrazine-2-carboxylate were dissolved in 2 ml of DMF. 72mg (0.64 mmol) of potassium tert-butoxide were added in portions to thesolution. The reaction mixture was stirred at RT overnight, and then 1.3ml (1.3 mmol) of 1 M sodium hydroxide solution were added. Afterstirring at 80° C. for 1 h and cooling to RT, the mixture was adjustedto pH 1-2 with 1 M hydrochloric acid. The mixture was extracted withethyl acetate, and the organic phase was removed and washed withsaturated sodium chloride solution. After the organic phase had beendried over sodium sulfate and the solvent had been removed on a rotaryevaporator, the residue was taken up in a little DMF and purified bymeans of preparative HPLC (method 6). After the solvent-water mixturehad been removed, the residue was taken up in a little acetonitrile,water was added and then the mixture was lyophilized. Since solventresidues were still present, the lyophilizate was redissolved indichloromethane and ethyl acetate, water was added again and the mixturewas lyophilized again. The resulting lyophilizate was redissolved onceagain in dichloromethane and tert-butanol, water was added and themixture was lyophilized again. The lyophilizate thus obtained was driedat 100° C. under high vacuum for a total 9 h. In this way, 39 mg (29% oftheory, 90% purity) of the title compound were obtained.

¹H-NMR (600 MHz, DMSO-d₆): δ [ppm]=13.54 (br. s, 1H), 12.03 (s, 1H),9.71 (s, 1H), 9.01 (s, 1H), 8.10 (d, 1H), 8.04 (d, 1H), 7.93 (dd, 1H),7.66-7.60 (m, 2H), 7.58-7.50 (m, 3H), 2.41 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=0.96 min, m/z=463/465 [M+H]⁺.

Example 45-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}pyrimidine-2-carboxylicAcid

A solution of 23 mg (0.05 mmol) of the compound from example 36A in 0.7ml of a THF/methanol mixture (5:1) was admixed with 0.24 ml (0.24 mmol)of 1 M sodium hydroxide solution and stirred under reflux for 1 h. Aftercooling to RT, the mixture, without further workup, was purified bymeans of preparative HPLC (method 15). The acetonitrile-water mixturewas removed on a rotary evaporator and the residue was dried underreduced pressure overnight. 10 mg (22% of theory, 98% purity) of thetitle compound were obtained.

¹H-NMR (400 MHz, CD₃OD): [ppm]=9.41 (br. s, 2H), 8.12 (s, 1H), 8.05 (d,1H), 7.95 (d, 1H), 7.71-7.51 (m, 5H), 2.50 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=0.90 min, m/z=463/465 [M+H]⁺.

Example 55-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-6-methylpyridine-2-carboxylicAcid

To 250 mg (0.64 mmol) of the compound from example 2A were added 10 mlof THF, 127 mg (0.77 mmol) of methyl5-amino-6-methylpyridine-2-carboxylate and 56 mg (1.40 mmol) of sodiumhydride (60% in mineral oil). The reaction mixture was stirred at RT fortwo days, then water was added, and the mixture was acidified withhydrochloric acid and extracted with ethyl acetate. The organic phasewas separated off and the solvent was removed on a rotary evaporator.The residue was purified by means of preparative HPLC (method 11). 41 mg(13% of theory, 100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.76 (s, 1H), 8.43 (d, 1H),8.07-8.02 (m, 3H), 7.97-7.94 (m, 1H), 7.66-7.64 (m, 2H), 7.59-7.49 (m,3H), 2.58 (s, 3H), 2.48 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=0.96 min, m/z=476/478 [M+H]⁺.

Example 66-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-5-fluoronicotinicAcid

To a solution of 156 mg (0.31 mmol) of the compound from example 37A in3.9 ml of THF and 0.8 ml of methanol were added, at RT, 1.54 ml (1.54mmol) of 1 M sodium hydroxide solution, and the mixture was stirredunder reflux for 1 h. After cooling to RT, the organic solvent wasremoved. The remaining residue was diluted with water, and the mixturewas acidified with 1 M hydrochloric acid while stirring. The solidsformed were filtered off and washed twice with water. Drying underreduced pressure gave 131 mg (89% of theory, purity 100%) of the titlecompound.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=13.67 (br. s, 1H), 11.60 (s, 1H), 8.86(br. s, 1H), 8.30 (d, 1H), 8.10-7.89 (m, 3H), 7.67-7.60 (m, 2H),7.58-7.49 (m, 3H), 2.47 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=0.99 min, m/z=480/482 [M+H]⁺.

Example 74-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoicAcid

100 mg (0.20 mmol) of the compound from example 38A were dissolved in2.5 ml of THF and 0.5 ml of methanol. 0.61 ml (0.61 mmol) of 1 M sodiumhydroxide solution was added to the solution. The reaction mixture wasstirred under reflux for 1 h. The volume of the solution was thenreduced on a rotary evaporator, and the concentrated solution wasadjusted to pH 3 with 0.6 ml of 1 M hydrochloric acid. The mixture wasdiluted with 5 ml of water, and the precipitated solids were filteredoff. The solids were washed with water and dried under reduced pressure.94 mg (97% of theory, 100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=13.27 (br. s, 1H), 11.04 (s, 1H), 8.17(t, 1H), 8.05 (d, 1H), 7.99 (d, 1H), 7.94 (dd, 1H), 7.88 (dd, 1H), 7.80(dd, 1H), 7.65-7.61 (m, 2H), 7.58-7.50 (m, 3H), 2.44 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.08 min, m/z=479/481 [M+H]⁺.

Example 84-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-fluorobenzoicacid

To 95 mg (0.19 mmol) of the compound from example 41A were added 2 ml ofTHF and 1.9 ml of 4 M sodium hydroxide solution. The reaction mixturewas stirred at 80° C. overnight. Thereafter, the organic phase wasremoved and, without further workup, purified by means of preparativeHPLC (method 9). 16 mg (17% of theory, 100% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=11.38 (s, 1H), 8.07-8.04 (m, 1H),7.96-7.92 (m, 3H), 7.85 (dd, 1H), 7.65-7.62 (m, 2H), 7.58-7.50 (m, 4H),2.40 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.11 min, m/z=479/481 [M+H]⁺.

Example 94-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-chlorobenzoicacid

To a solution of 1.53 g (3.00 mmol) of the compound from example 42A in38 ml of THF and 8 ml of methanol were added, at RT, 15 ml (15 mmol) of1 M sodium hydroxide solution, and the mixture was stirred under refluxfor 1 h. After cooling to RT, the organic solvent was removed. Theremaining residue was diluted with water, and the mixture was acidifiedwith 1 M hydrochloric acid while stirring. The solids present werefiltered off and washed twice with water and once with tert-butyl methylether. Drying under reduced pressure gave 1.40 g (94% of theory, 100%purity) of the title compound.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.34 (br. s, 1H), 10.93 (s, 1H),8.13-7.99 (m, 5H), 7.94 (dd, 1H), 7.68-7.60 (m, 2H), 7.59-7.49 (m, 3H),2.48 (s, 3H, partially hidden).

LC/MS (Method 1, ESIpos): R_(t)=1.11 min, m/z=495/497 [M+H]⁺.

Example 103-Bromo-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}benzoicacid

To a solution of 120 mg (0.22 mmol) of the compound from example 43A in2.5 ml of THF and 0.5 ml of methanol was added, at RT, 1.0 ml (1.0 mmol)of 1 M sodium hydroxide solution, and the mixture was stirred underreflux for 1 h. After cooling to RT, the mixture was introduced into 30ml of water and then acidified with 1 M hydrochloric acid whilestirring. The solids present were filtered off and washed twice withwater and once with tert-butyl methyl ether. Drying under reducedpressure gave 113 mg (95% of theory, purity 98%) of the title compound.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.35 (s, 1H), 10.88 (s, 1H), 8.23(d, 1H), 8.14 (d, 1H), 8.09-8.02 (m, 2H), 8.01-7.97 (m, 1H), 7.94 (dd,1H), 7.66-7.61 (m, 2H), 7.59-7.49 (m, 3H), 2.50 (s, 3H, hidden).

LC/MS (Method 1, ESIpos): R_(t)=1.13 min, m/z=539/541/543 [M+H]⁺.

Example 114-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-iodobenzoicAcid

100 mg (0.26 mmol) of the compound from example 2A and 71 mg (0.26 mmol)of methyl 4-amino-3-iodobenzoate were dissolved in 2 ml of DMF.Subsequently, 72 mg (0.64 mmol) of potassium tert-butoxide were added inportions, and the reaction mixture was stirred at RT overnight.Thereafter, the mixture was admixed with 1.3 ml (1.3 mmol) of 1 M sodiumhydroxide solution and stirred at 80° C. for 1 h. After cooling to RT,the mixture, without further workup, was purified by means ofpreparative HPLC (method 6). After the solvent-water mixture had beenremoved, the mixture was dried under reduced pressure overnight. 81 mg(53% of theory, 99% purity) of the title compound were obtained.

¹H-NMR (500 MHz, DMSO-d₆): [ppm]=13.30 (br. s, 1H), 10.77 (s, 1H), 8.45(d, 1H), 8.17 (d, 1H), 8.10-8.01 (m, 2H), 7.94 (dd, 1H), 7.86 (d, 1H),7.68-7.60 (m, 2H), 7.60-7.49 (m, 3H), 2.53 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.11 min, m/z=586/588 [M+H]⁺.

Example 124-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3,5-difluorobenzoicAcid

500 mg (1.28 mmol) of the compound from example 2A and 286 mg (1.53mmol) of methyl 4-amino-3,5-difluorobenzoate were dissolved in 10 ml ofTHF, and 112 mg (2.80 mmol) of sodium hydride (60% in mineral oil) wereadded at RT. After stirring overnight, the solvent was removed on arotary evaporator. The residue, without further workup, was purified bymeans of preparative HPLC (method 13). The product thus obtained wasstirred with acetonitrile, and the resulting solids were filtered offand washed with acetonitrile. Drying under reduced pressure gave 124 mg(18% of theory, purity 94%) of the title compound.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=10.69 (s, 1H), 8.08 (d, 1H), 8.06-8.03(d, 1H), 7.96-7.94 (dd, 1H), 7.65-7.63 (m, 2H), 7.58-7.50 (m, 5H), 2.48(s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.08 min, m/z=497/499 [M+H]⁺.

Example 134-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3,5-dichlorobenzoicAcid

To a solution of 62 mg (0.11 mmol) of the compound from example 44A in1.4 ml of THF and 0.3 ml of methanol was added, at RT, 0.56 ml (0.56mmol) of 1 M sodium hydroxide solution, and the mixture was stirredunder reflux for 1 h. After cooling to RT, the organic solvent wasremoved. The remaining residue was diluted with water, and the mixturewas acidified with 1 M hydrochloric acid while stirring. The solidsformed were filtered off and washed twice with water. After drying underair, the solids were taken up in DMSO and purified by means ofpreparative HPLC (method 5). The combined product-containing fractionswere concentrated, the residue was taken up in dichloromethane/methanol,and the mixture was concentrated again. After the residue had been driedunder reduced pressure, 20 mg (34% of theory, 100% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=13.68 (br. s, 1H), 11.22 (s, 1H), 8.42(d, 1H), 8.16-8.01 (m, 3H), 7.95 (dd, 1H), 7.67-7.61 (m, 2H), 7.59-7.48(m, 3H), 2.58 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.10 min, m/z=529/531/533 [M+H]⁺.

Example 144-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-methylbenzoicAcid

To 128 mg (0.26 mmol) of the compound from example 45A were added 3.3 mlof THF and then a solution of 9 mg (0.39 mmol) of lithium hydroxide in1.1 ml of water. The reaction mixture was first stirred at RT for twodays, then 2.6 ml of 4 M sodium hydroxide solution were added, and themixture was stirred at RT for a further 24 h. Thereafter, the reactionmixture was heated to 100° C. for 3 h. After cooling to RT, the reactionmixture was adjusted to pH 1-2 with hydrochloric acid. The precipitatedsolids were filtered off with suction, washed with water and dried underreduced pressure. 70 mg (56% of theory, 99% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=10.57 (s, 1H), 8.06 (d, 1H), 8.02 (d,1H), 7.95 (dd, 1H), 7.92-7.87 (m, 3H), 7.66-7.64 (m, 2H), 7.59-7.51 (m,3H), 2.54 (s, 3H), 2.38 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.09 min, m/z=475/477 [M+H]⁺.

Example 154-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(trifluoromethyl)benzoicAcid

To a solution of 300 mg (0.87 mmol) of the compound from example 1A in 3ml of DMF were added, at RT, 267 mg (0.96 mmol) of4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride and211 mg (0.96 mmol) of methyl 4-amino-3-(trifluoromethyl)benzoate. Themixture was stirred at RT for 20 h. Subsequently, about 100 mg (about2.63 mmol) of sodium hydride (60% dispersion in mineral oil) weregradually added in portions, and the mixture was first stirred at RT for1 h and then left to stand at RT for 2 days. Thereafter, the mixture wasdiluted with ethyl acetate and washed with water. The aqueous phase wasextracted once with ethyl acetate, and the combined organic phases weredried over magnesium sulfate, filtered and concentrated. The residue waspurified by means of preparative HPLC (method 5). The combinedproduct-containing fractions were concentrated down to a residual volumeof aqueous phase and extracted twice with ethyl acetate. The combinedorganic phases were again dried over magnesium sulfate, filtered andconcentrated. The residue was taken up in a methanol/dichloromethanemixture, concentrated again and finally dried under reduced pressure.153 mg (33% of theory, 100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.54 (br. s, 1H), 10.95 (s, 1H),8.35 (dd, 1H), 8.31-8.29 (m, 1H), 8.08-8.00 (m, 3H), 7.95 (dd, 1H),7.67-7.61 (m, 2H), 7.60-7.50 (m, 3H), 2.50 (s, 3H, hidden).

LC/MS (Method 1, ESIpos): R_(t)=1.17 min, m/z=529/531 [M+H]⁺.

Example 164-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-cyanobenzoicacid

To 250 mg (0.64 mmol) of the compound from example 2A and 133 mg (0.70mmol) of ethyl 4-amino-3-cyanobenzoate were added 2 ml of THF and 56 mg(1.40 mmol) of sodium hydride (60% in mineral oil). The reaction mixturewas stirred at RT overnight. Then the mixture was admixed with water,acidified with 2 M hydrochloric acid and extracted with ethyl acetate.The organic phase was removed and washed with saturated sodium chloridesolution. After the organic phase had been dried over sodium sulfate andthe solvent had been removed, the residue was stirred with acetonitrile.The solids were filtered off, washed with acetonitrile and then purifiedby means of preparative HPLC (method 8). 102 mg (31% of theory, 96%purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=13.54 (br. s, 1H), 11.54 (s, 1H), 8.39(d, 1H), 8.32 (dd, 1H), 8.17 (d, 1H), 8.06 (d, 1H), 7.96 (dd, 1H), 7.91(d, 1H), 7.65-7.63 (m, 2H), 7.59-7.51 (m, 3H), 2.49 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.07 min, m/z=486/488 [M+H]⁺.

Example 174-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-nitrobenzoicAcid

To 100 mg (0.26 mmol) of the compound from example 2A and 60 mg (0.31mmol) of methyl 4-amino-3-nitrobenzoate were added 2 ml of THF. Then, atRT, 22 mg (0.56 mmol) of sodium hydride (60% in mineral oil) were added.After stirring at RT overnight, the reaction mixture was admixed with afew drops of water and, without further workup, purified by means ofpreparative HPLC (method 8). 110 mg (85% of theory, 100% purity) of thetitle compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=13.62 (br. s, 1H), 11.65 (s, 1H), 8.45(d, 1H), 8.32-8.29 (dd, 1H), 8.12 (d, 1H), 8.06 (d, 1H), 7.96 (dd, 1H),7.81 (d, 1H), 7.65-7.61 (m, 2H), 7.59-7.51 (m, 3H), 2.43 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.15 min, m/z=507 [M+H]⁺.

Example 183-Amino-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}benzoicAcid

To 282 mg (0.56 mmol) of the compound from example 17 were added 1.6 mlof acetic acid, 2.5 ml of ethanol, 2.5 ml of water and 628 mg (2.79mmol) of tin(II) chloride. The reaction mixture was stirred at 80° C.for 3 h and then, without further workup, purified by means ofpreparative HPLC (method 13). 211 mg (80% of theory, 100% purity) of thetitle compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=12.69 (br. s, 1H), 10.30 (s, 1H), 8.05(d, 1H), 8.01 (d, 1H), 7.94 (dd, 1H), 7.74 (d, 1H), 7.65-7.63 (m, 2H),7.58-7.50 (m, 3H), 7.47 (d, 1H), 7.28 (dd, 1H), 5.25 (br. s, 2H), 2.46(s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=0.97 min, m/z=476/478 [M+H]⁺.

Example 193-Acetamido-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}benzoicAcid

To 100 mg (0.21 mmol) of the compound from example 18 were added 1 ml ofDMF and 0.12 ml (0.84 mmol) of triethylamine. At 0° C., 0.02 ml (0.25mmol) of acetyl chloride were added dropwise. After 5 min, the ice bathwas removed, and the reaction mixture was stirred at RT overnight. Themixture was then, without further workup, purified by means ofpreparative HPLC (method 8). The acetonitrile-water mixture was removedon a rotary evaporator, and the resulting residue was purified furtherby another preparative HPLC (method 13). 14 mg (13% of theory, 100%purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=13.07 (br. s, 1H), 10.60 (s, 1H), 9.64(s, 1H), 8.04-7.99 (m, 4H), 7.93 (dd, 1H), 7.82 (d, 1H), 7.63-7.61 (m,2H), 7.57-7.50 (m, 3H), 2.45 (s, 3H), 2.04 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=0.99 min, m/z=518/520 [M+H]⁺.

Example 204-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-[(ethylcarbamoyl)amino]benzoicAcid

To 100 mg (0.21 mmol) of the compound from example 18 were added 1 ml ofDMF and 0.12 ml (0.84 mmol) of triethylamine. At 0° C., 0.02 ml (0.25mmol) of ethyl isocyanate were added dropwise. After 5 min, the ice bathwas removed, and the reaction mixture was stirred at RT for 3 h. Theprecipitated solids were then filtered off, washed with acetonitrile,dried under reduced pressure and then purified by means of preparativeHPLC (method 14). 38 mg (33% of theory, 100% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.72 (s, 1H), 8.12 (s, 1H),8.06-8.01 (m, 3H), 7.93 (dd, 1H), 7.83 (d, 1H), 7.70 (d, 1H), 7.63-7.61(m, 2H), 7.58-7.45 (m, 3H), 6.76 (m, 1H), 3.06 (m, 2H), 2.46 (s, 3H),0.98 (t, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.03 min, m/z=547/549 [M+H]⁺.

Example 214-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-methoxybenzoicAcid

To a solution of 660 mg (1.31 mmol) of the compound from example 46A in16.5 ml of THF and 3.5 ml of methanol were added, at RT, 6.6 ml (6.6mmol) of 1 M sodium hydroxide solution, and the mixture was stirredunder reflux for 1 h. After cooling to RT, the organic solvent wasremoved. The remaining residue was diluted with water, and the mixturewas acidified with 1 M hydrochloric acid while stirring. The solidspresent were filtered off and washed twice with water and once withtert-butyl methyl ether. Drying under reduced pressure gave 599 mg (93%of theory, purity 100%) of the title compound.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.02 (br. s, 1H), 10.50 (br. s, 1H),8.17-7.84 (m, 4H), 7.75-7.43 (m, 7H), 3.93 (s, 3H), 2.43 (s, 3H,partially hidden).

LC/MS (Method 1, ESIpos): R_(t)=1.09 min, m/z=491/493 [M+H]+.

Example 224-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-hydroxybenzoicAcid

To a suspension of 90 mg (0.18 mmol) of the compound from example 21 in2 ml of dichloromethane was added, at 0° C., 0.55 ml (0.55 mmol) of a 1M solution of boron tribromide in dichloromethane.

The mixture was stirred at RT for 2 h. The reaction mixture thusobtained was then combined with an analogously obtained reaction mixturefrom a proceeding experiment [amount of compound from example 21 used:10 mg (0.02 mmol)]. After the solvent had been removed, the residue wastaken up in DMSO and purified by means of preparative HPLC (method 5).The combined product-containing fractions were concentrated, the residuewas taken up in dichloromethane, and the mixture was concentrated again.After drying under reduced pressure, 86 mg (100% purity, 89% of theory,based on a total of 100 mg (0.20 mmol) of the compound from example 21)of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=12.79 (br. s, 1H), 10.37 (s, 1H), 10.35(s, 1H), 8.09-7.99 (m, 3H), 7.91 (dd, 1H), 7.66-7.59 (m, 2H), 7.59-7.46(m, 5H), 2.43 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=0.99 min, m/z=477/479 [M+H]⁺.

Example 234-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(trifluoromethoxy)benzoicacid

A solution of 75 mg (0.13 mmol) of the compound from example 47A in 2 mlof a THF/methanol mixture (5:1) was admixed with 0.65 ml (0.65 mmol) of1 M sodium hydroxide solution and stirred under reflux for 1 h. Aftercooling to RT, the mixture, without further workup, was purified bymeans of preparative HPLC (method 6). The acetonitrile-water mixture wasremoved on a rotary evaporator and the residue was dried under reducedpressure overnight. 49 mg (69% of theory, 100% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=13.42 (br. s, 1H), 11.14 (s, 1H), 8.29(d, 1H), 8.12-8.01 (m, 2H), 7.98-7.91 (m, 3H), 7.68-7.60 (m, 2H),7.60-7.49 (m, 3H), 2.43 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.15 min, m/z=545/547 [M+H]⁺.

Example 244-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(methylsulfanyl)benzoicAcid

To a solution of 100 mg (0.19 mmol) of the compound from example 48A in2.5 ml of THF and 0.5 ml of methanol were added, at RT, 0.50 ml (0.50mmol) of 1 M sodium hydroxide solution, and the mixture was stirredunder reflux for 1 h. After cooling to RT, the organic solvent wasremoved. The remaining residue was diluted with water, and the mixturewas acidified with 1 M hydrochloric acid while stirring. After stirringfor a few minutes, the solids present were filtered off and washed twicewith water. Drying under reduced pressure gave 88 mg (86% of theory,purity 95%) of the title compound.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.17 (br. s, 1H), 10.70 (s, 1H),8.27 (d, 1H), 8.04 (d, 1H), 7.96-7.90 (m, 2H), 7.86 (dd, 1H), 7.69 (d,1H), 7.66-7.60 (m, 2H), 7.59-7.49 (m, 3H), 2.56 (s, 3H, partiallyhidden), 2.50 (s, 3H, partially hidden).

LC/MS (Method 1, ESIpos): R_(t)=1.09 min, m/z=507/509 [M+H]⁺.

Example 254-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(methylsulfinyl)benzoicAcid

To a solution of 140 mg (0.26 mmol) of the compound from example 49A in3.5 ml of THF and 0.7 ml of methanol were added, at RT, 1.31 ml (1.31mmol) of 1 M sodium hydroxide solution, and the mixture was stirredunder reflux for 1 h. After cooling to RT, 0.10 ml (1.31 mmol) oftrifluoroacetic acid was added. Subsequently, the mixture was purifiedby means of preparative HPLC (method 5). The combined product-containingfractions were concentrated, the residue was taken up indichloromethane, and the mixture was concentrated again. After theresidue had been dried under reduced pressure, 126 mg (93% of theory,100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.39 (br. s, 1H), 11.22 (s, 1H),8.53 (d, 1H), 8.20 (dd, 1H), 8.11-8.03 (m, 2H), 7.97 (dd, 1H), 7.81 (d,1H), 7.67-7.61 (m, 2H), 7.61-7.50 (m, 3H), 2.92 (s, 3H), 2.50 (s, 3H,hidden).

LC/MS (Method 1, ESIpos): R_(t)=0.97 min, m/z=523/525 [M+H]⁺.

Example 264-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(methylsulfonyl)benzoicAcid

To a solution of 100 mg (0.18 mmol) of the compound from example 50A in2.5 ml of THF and 0.5 ml of methanol were added, at RT, 0.91 ml (0.91mmol) of 1 M sodium hydroxide solution, and the mixture was stirredunder reflux for 1 h. After cooling to RT, 0.07 ml (0.91 mmol) oftrifluoroacetic acid was added. Subsequently, the mixture was purifiedby means of preparative HPLC (method 5). The combined product-containingfractions were concentrated, the residue was taken up indichloromethane, and the mixture was concentrated again. After theresidue had been dried under reduced pressure, 83 mg (85% of theory,100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.55 (br. s, 1H), 10.75 (s, 1H),8.54 (d, 1H), 8.37 (dd, 1H), 8.32-8.24 (m, 2H), 8.04 (d, 1H), 7.94 (dd,1H), 7.67-7.61 (m, 2H), 7.60-7.49 (m, 3H), 3.41 (s, 3H), 2.50 (s, 3H,hidden).

LC/MS (Method 1, ESIpos): R_(t)=1.08 min, m/z=539/541 [M+H]⁺.

Example 274-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-5-(ethylsulfonyl)-2-methoxybenzoicAcid

To a solution of 221 mg (0.37 mmol) of the compound from example 51A in4.7 ml of THF and 1.0 ml of methanol were added, at RT, 1.86 ml (1.86mmol) of 1 M sodium hydroxide solution, and the mixture was stirredunder reflux for 1 h. After cooling to RT, the organic solvent wasremoved. The remaining residue was diluted with water, and the mixturewas acidified with 1 M hydrochloric acid while stirring. The solidsformed were filtered off and washed twice with water. Drying underreduced pressure gave 180 mg (84% of theory, purity 100%) of the titlecompound.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.03 (br. s, 1H), 10.61 (s, 1H),8.27-8.22 (m, 2H), 8.12 (s, 1H), 8.08-8.01 (m, 1H), 7.95 (dd, 1H),7.68-7.61 (m, 2H), 7.60-7.49 (m, 3H), 4.02 (s, 3H), 3.47-3.36 (m, 2H,partially hidden), 2.49 (s, 3H, hidden), 1.14 (t, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.12 min, m/z=583/585 [M+H]⁺.

Example 284-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-[(trifluoromethyl)sulfanyl]benzoicAcid

A mixture of 50 mg (0.09 mmol) of the compound from example 53A in 1.6ml of THF and 0.3 ml of methanol was admixed with 0.32 ml (0.32 mmol) of1 M sodium hydroxide solution and then stirred under reflux for 1 h.After cooling to RT, the mixture was adjusted to pH 4 with about 0.03 mlof trifluoroacetic acid and, without further workup, was purified bymeans of preparative HPLC (method 5). After the solvent-water mixturehad been removed, the residue was taken up in dichloromethane, themixture was concentrated again and the residue was dried under reducedpressure. 35 mg (72% of theory, 100% purity) of the title compound wereobtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.46 (br. s, 1H), 11.34 (br. s, 1H),8.50-7.80 (m, 6H), 7.73-7.33 (m, 5H), 2.47 (s, 3H, partially hidden).

LC/MS (Method 1, ESIpos): R_(t)=1.19 min, m/z=561/563 [M+H]⁺.

Example 293-Fluoro-4-{[(6-fluoro-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}benzoicAcid

To a solution of 184 mg (0.43 mmol) of the compound from example 54A in5.5 ml of THF and 1.1 ml of methanol were added, at RT, 2.14 ml (2.14mmol) of 1 M sodium hydroxide solution, and the mixture was stirredunder reflux for 1 h. After cooling to RT, the organic solvent wasremoved. The aqueous solution that remained was introduced into 20 ml of1 M hydrochloric acid while stirring. After stirring for a few minutes,the solids formed were filtered off and washed twice with water and oncewith pentane. Drying under reduced pressure gave 148 mg (83% of theory,purity 100%) of the title compound.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.24 (br. s, 1H), 11.03 (s, 1H),8.22 (t, 1H), 8.17 (dd, 1H), 7.88 (dd, 1H), 7.80 (dd, 1H), 7.73 (td,1H), 7.64-7.59 (m, 2H), 7.59-7.49 (m, 4H), 2.43 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=0.99 min, m/z=419 [M+H]⁺.

Example 303-Fluoro-4-{[(6-iodo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}benzoicAcid

100 mg (0.23 mmol) of the compound from example 6A and 39 mg (0.23 mmol)of methyl 4-amino-3-fluorobenzoate were dissolved in 1.7 ml of DMF. 64mg (0.57 mmol) of potassium tert-butoxide were added in portions to thesolution. The reaction mixture was stirred at RT for 1 h, and then 1.3ml (1.3 mmol) of 1 M sodium hydroxide solution were added. The mixturewas then stirred at 80° C. for 1 h. After cooling to RT, the mixture,without further workup, was purified by means of preparative HPLC(method 6). After the solvent-water mixture had been removed and theresidue had been dried under reduced pressure, 76 mg (62% of theory, 98%purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=13.25 (br. s, 1H), 11.04 (s, 1H), 8.19(t, 1H), 8.18 (d, 1H), 8.06 (dd, 1H), 7.93-7.84 (m, 2H), 7.82 (dd, 1H),7.66-7.59 (m, 2H), 7.59-7.47 (m, 3H), 2.42 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.07 min, m/z=527 [M+H]⁺.

Example 314-{[(3,6-Dimethyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoicacid

To a solution of 124 mg (0.27 mmol, 93% purity) of the compound fromexample 55A in 3.5 ml of THF and 0.7 ml of methanol were added, at RT,1.35 ml (1.35 mmol) of 1 M sodium hydroxide solution, and the mixturewas stirred under reflux for 1 h. After cooling to RT, 0.10 ml (1.35mmol) of trifluoroacetic acid was added. Subsequently, the mixture waspurified by means of preparative HPLC (method 5). The combinedproduct-containing fractions were concentrated, the residue was taken upin dichloromethane, and the mixture was concentrated again. Drying underreduced pressure gave 83 mg (75% of theory, purity 100%) of the titlecompound.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.17 (br. s, 1H), 10.99 (s, 1H),8.24 (t, 1H), 7.98 (d, 1H), 7.88 (dd, 1H), 7.80 (dd, 1H), 7.68-7.58 (m,4H), 7.58-7.47 (m, 3H), 2.53 (s, 3H, partially hidden), 2.40 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.01 min, m/z=415 [M+H]⁺.

Example 324-{[(6-Ethyl-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoicAcid

To a solution of 186 mg (0.38 mmol, 91% purity) of the compound fromexample 56A in 5.0 ml of THF and 1.0 ml of methanol were added, at RT,1.92 ml (1.92 mmol) of 1 M sodium hydroxide solution, and the mixturewas stirred under reflux for 1 h. After cooling to RT, 0.15 ml (2.00mmol) of trifluoroacetic acid was added. After being left to standovernight, the mixture was purified by means of preparative HPLC (Method5). The combined product-containing fractions were concentrated, theresidue was taken up in dichloromethane, and the mixture wasconcentrated again. Drying under reduced pressure gave 139 mg (85% oftheory, purity 100%) of the title compound.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=13.30 (br. s, 1H), 11.25-10.78 (m, 1H),8.20 (t, 1H), 8.03 (d, 1H), 7.89 (dd, 1H), 7.81 (dd, 1H), 7.72 (dd, 1H),7.66-7.60 (m, 3H), 7.59-7.49 (m, 3H), 2.84 (q, 2H), 2.41 (s, 3H), 1.27(t, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.06 min, m/z=429 [M+H]+.

Example 333-Fluoro-4-{[(6-isopropyl-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}benzoicAcid

To 108 mg (0.24 mmol) of the compound from example 57A were added 2.4 mlof THF and 2.4 ml of 4 M sodium hydroxide solution. The reaction mixturewas stirred at 60° C. for 10 h. Thereafter, the organic phase wasremoved and, without further workup, purified by means of preparativeHPLC (method 9). The acetonitrile-water mixture was removed on a rotaryevaporator and the residue was stirred with acetonitrile. The solidswere filtered off and dried under reduced pressure. 45 mg (43% oftheory, 100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.26 (br. s, 1H), 11.01 (s, 1H),8.14 (t, 1H), 8.02 (d, 1H), 7.92-7.71 (m, 3H), 7.67-7.44 (m, 6H),3.20-3.04 (m, 1H), 2.41 (s, 3H), 1.29 (d, 6H).

LC/MS (Method 1, ESIpos): R_(t)=1.10 min, m/z=443 [M+H]⁺.

Example 343-Fluoro-4-({[3-methyl-2-phenyl-6-(trifluoromethyl)quinolin-4-yl]carbonyl}amino)benzoicacid

To 105 mg (0.22 mol) of the compound from example 58A were added 2.2 mlof THF and 2.2 ml of 4 M sodium hydroxide solution. The reaction mixturewas stirred at 60° C. overnight. Thereafter, the organic phase wasremoved and, without further workup, purified by means of preparativeHPLC (method 9). After the solvent-water mixture had been removed, themixture was dried at 60° C. under reduced pressure overnight. 97 mg (95%of theory, 100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=13.30 (br. s, 1H), 11.13 (s, 1H), 8.32(d, 1H), 8.18-8.14 (m, 2H), 8.08 (dd, 1H), 7.90 (dd, 1H), 7.83 (dd, 1H),7.68-7.66 (m, 2H), 7.61-7.53 (m, 3H), 2.48 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.13 min, m/z=469 [M+H]⁺.

Example 353-Fluoro-4-({[3-methyl-2-phenyl-6-(trifluoromethoxy)quinolin-4-yl]carbonyl}amino)benzoicAcid

To a solution of 150 mg (0.27 mmol, 91% purity) of the compound fromexample 59A in 3.5 ml of THF and 0.7 ml of methanol were added, at RT,1.38 ml (1.38 mmol) of 1 M sodium hydroxide solution, and the mixturewas stirred under reflux for 1 h. After cooling to RT, 0.11 ml (1.38mmol) of trifluoroacetic acid was added. Subsequently, the mixture waspurified by means of preparative HPLC (method 5). The combinedproduct-containing fractions were concentrated, the residue was taken upin dichloromethane, and the mixture was concentrated again. Drying underreduced pressure gave 115 mg (87% of theory, purity 100%) of the titlecompound.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=13.25 (br. s, 1H), 11.07 (s, 1H), 8.24(d, 1H), 8.16 (t, 1H), 7.89 (dd, 1H), 7.82 (dd, 2H), 7.74 (s, 1H),7.68-7.61 (m, 2H), 7.60-7.48 (m, 3H), 2.45 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.08 min, m/z=485 [M+H]⁺.

Example 363-Fluoro-4-({[3-methyl-2-phenyl-6-(trimethylsilyl)quinolin-4-yl]carbonyl}amino)benzoicAcid

To a mixture of 34 mg (0.06 mmol) of the compound from Example 60A in 1ml of dichloromethane was added 0.5 ml (6.49 mmol) of trifluoroaceticacid, and the mixture was stirred at RT for 1 h. Then the mixture wasconcentrated. The residue was taken up in DMSO and purified by means ofpreparative HPLC (method 5). The combined product-containing fractionswere concentrated, the residue was taken up in dichloromethane, and themixture was concentrated again. Drying under reduced pressure gave 25 mg(81% of theory, purity 100%) of the title compound.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=13.19 (br. s, 1H), 11.03 (s, 1H),8.11-7.99 (m, 3H), 7.97-7.87 (m, 2H), 7.83 (d, 1H), 7.67-7.61 (m, 2H),7.60-7.47 (m, 3H), 2.44 (s, 3H), 0.32 (s, 9H).

LC/MS (Method 1, ESIpos): R_(t)=1.19 min, m/z=473 [M+H]⁺.

Example 374-({[6-Bromo-3-(fluoromethyl)-2-phenylquinolin-4-yl]carbonyl}amino)-3-fluorobenzoicAcid

To a solution of 60 mg (0.12 mmol) of the compound from example 63A in1.5 ml of THF and 0.3 ml of methanol was added, at RT, 0.59 ml (0.59mmol) of 1 M sodium hydroxide solution, and the mixture was stirredunder reflux for 30 min. After cooling to RT, 0.05 ml (0.60 mmol) oftrifluoroacetic acid was added. Subsequently, the mixture was purifiedby means of preparative HPLC (method 12). 39 mg (66% of theory, 100%purity) of the title compound were obtained.

¹H-NMR (500 MHz, DMSO-d₆): [ppm]=13.23 (br. s, 1H), 11.16 (s, 1H), 8.23(t, 1H), 8.15-8.10 (m, 2H), 8.07 (dd, 1H), 7.90 (dd, 1H), 7.82 (dd, 1H),7.70-7.64 (m, 2H), 7.63-7.54 (m, 3H), 5.57 (dd, 2H).

LC/MS (Method 1, ESIpos): R_(t)=1.05 min, m/z=497/499 [M+H]⁺.

Example 384-({[6-Bromo-3-(difluoromethyl)-2-phenylquinolin-4-yl]carbonyl}amino)-3-fluorobenzoicacid

To a solution of 20 mg (0.04 mmol) of the compound from example 64A in0.6 ml of THF and 0.13 ml of methanol was added, at RT, 0.19 ml (0.19mmol) of 1 M sodium hydroxide solution, and the mixture was stirredunder reflux for 30 min. After cooling to RT, 0.015 ml (0.19 mmol) oftrifluoroacetic acid was added. Subsequently, the mixture was purifiedby means of preparative HPLC (method 5). The combined product-containingfractions were concentrated, the residue was taken up indichloromethane, and the mixture was concentrated again. Drying underreduced pressure gave 11 mg (54% of theory, purity 100%) of the titlecompound.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=13.24 (br. s, 1H), 11.13 (s, 1H), 8.26(t, 1H), 8.18-8.09 (m, 3H), 7.90 (dd, 1H), 7.81 (dd, 1H), 7.65-7.54 (m,5H), 7.09 (t, 1H).

LC/MS (Method 1, ESIpos): R_(t)=1.05 min, m/z=515/517 [M+H]⁺.

Example 394-{[(6-Bromo-3-ethyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoicacid

To a solution of 187 mg (0.37 mmol) of the compound from example 65A in5.8 ml of THF and 1.2 ml of methanol were added, at RT, 1.86 ml (1.86mmol) of 1 M sodium hydroxide solution, and the mixture was stirredunder reflux for 30 min. After cooling to RT, the organic solvent wasremoved by distillation, and 0.14 ml (1.86 mmol) of trifluoroacetic acidwas added to the aqueous phase that remained. The solids formed werefiltered off, washed twice with 1 ml of water and dried under reducedpressure. 178 mg (98% of theory, 100% purity) of the title compound wereobtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=10.99 (s, 1H), 8.05-7.97 (m, 3H), 7.94(dd, 1H), 7.84 (dd, 1H), 7.76 (dd, 1H), 7.60-7.48 (m, 5H), 2.83 (d, 2H),0.99 (t, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.07 min, m/z=493/495 [M+H]⁺.

Example 404-{[(6-Bromo-2-phenyl-3-propylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoicAcid

To a solution of 139 mg (0.27 mmol) of the compound from example 66A in4.2 ml of THF and 0.9 ml of methanol were added, at RT, 1.34 ml (1.34mmol) of 1 M sodium hydroxide solution, and the mixture was stirredunder reflux for 3 h. After cooling to RT, the organic solvent wasremoved by distillation, and 0.10 ml (1.34 mmol) of trifluoroacetic acidwas added to the aqueous phase that remained. The solids formed werefiltered off, washed twice with 1 ml of water and dried under reducedpressure. 86 mg (64% of theory, 100% purity) of the title compound wereobtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=10.74 (s, 1H), 8.04-7.99 (m, 2H), 7.94(dd, 1H), 7.74 (dd, 1H), 7.70-7.62 (m, 2H), 7.59-7.48 (m, 5H), 2.88-2.74(m, 2H), 1.40 (br. s, 2H), 0.69 (t, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.14 min, m/z=507/509 [M+H]⁺.

Example 414-{[(6-Bromo-7-chloro-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoicAcid

To a solution of 52 mg (0.10 mmol) of the compound from example 67A in1.3 ml of THF and 0.25 ml of methanol was added, at RT, 0.49 ml (0.49mmol) of 1 M sodium hydroxide solution, and the mixture was stirredunder reflux for 30 min. After cooling to RT, 0.04 ml (0.50 mmol) oftrifluoroacetic acid was added. The solids formed were filtered off andwashed twice with 1 ml of THF. After drying under reduced pressure, 13mg (26% of theory, 100% purity) of a first batch of the title compoundwere obtained. The filtrate was concentrated, and the residue was takenup in a mixture of DMSO, THF and water, and purified by means ofpreparative HPLC (method 12). In this way, 30 mg (60% of theory, 100%purity) of a second batch of the title compound were obtained.

¹H-NMR (500 MHz, DMSO-d₆): [ppm]=13.25 (br. s, 1H), 11.08 (s, 1H), 8.39(s, 1H), 8.23 (t, 1H), 8.20 (s, 1H), 7.89 (dd, 1H), 7.82 (dd, 1H),7.66-7.61 (m, 2H), 7.60-7.50 (m, 3H), 2.43 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.16 min, m/z=513/515 [M+H]⁺.

Example 424-{[(6,7-Dichloro-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoicAcid

100 mg (0.26 mmol) of the compound from example 22A and 44.4 mg (0.26mmol) of methyl 4-amino-3-fluorobenzoate were dissolved in 2 ml of DMF.73 mg (0.65 mmol) of potassium tert-butoxide were added in portions tothe solution. The reaction mixture was stirred at RT for 1 h, and then1.3 ml (1.3 mmol) of 1 M sodium hydroxide solution were added. Themixture was then stirred at 80° C. for 1 h. After cooling to RT, themixture, without further workup, was purified by means of preparativeHPLC (method 6). After the solvent-water mixture had been removed andthe residue had been dried under reduced pressure, 78 mg (59% of theory,93% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=13.25 (br. s, 1H), 11.07 (s, 1H), 8.41(s, 1H), 8.24 (t, 1H), 8.06 (s, 1H), 7.89 (dd, 1H), 7.81 (dd, 1H),7.69-7.60 (m, 2H), 7.60-7.48 (m, 3H), 2.43 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.15 min, m/z=469/471 [M+H]⁺.

Example 434-({[6-Bromo-2-(4-fluorophenyl)-3-methylquinolin-4-yl]carbonyl}amino)-3-fluorobenzoicAcid

To a solution of 173 mg (0.34 mmol) of the compound from example 68A in5.4 ml of THF and 1.1 ml of methanol were added, at RT, 1.71 ml (1.71mmol) of 1 M sodium hydroxide solution, and the mixture was stirredunder reflux for 30 min. After cooling to RT, the organic solvent wasremoved by distillation, and 0.13 ml (1.71 mmol) of trifluoroacetic acidwas added to the aqueous phase that remained. The solids formed werefiltered off, washed twice with 1 ml of water and dried under reducedpressure. 166 mg (99% of theory, 100% purity) of the title compound wereobtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=13.20 (br. s, 1H), 11.04 (s, 1H), 8.19(t, 1H), 8.05 (d, 1H), 7.99 (d, 1H), 7.94 (dd, 1H), 7.88 (dd, 1H), 7.81(dd, 1H), 7.73-7.65 (m, 2H), 7.42-7.33 (m, 2H), 2.44 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.06 min, m/z=497/499 [M+H]⁺.

Example 444-({[6-Bromo-2-(3-fluorophenyl)-3-methylquinolin-4-yl]carbonyl}amino)-3-fluorobenzoicAcid

To a solution of 96 mg (0.19 mmol) of the compound from example 69A in3.0 ml of THF and 0.6 ml of methanol was added, at RT, 0.95 ml (0.95mmol) of 1 M sodium hydroxide solution, and the mixture was stirredunder reflux for 3 h. After cooling to RT, the organic solvent wasremoved by distillation, and 0.07 ml (0.95 mmol) of trifluoroacetic acidwas added to the aqueous phase that remained. The solids formed werefiltered off, washed twice with 1 ml of water and dried under reducedpressure. Subsequently, the solids were taken up in DMSO and purified bymeans of preparative HPLC (method 12). 68 mg (72% of theory, 100%purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=13.25 (s, 1H), 11.05 (s, 1H), 8.21 (t,1H), 8.06 (d, 1H), 8.00 (d, 1H), 7.95 (dd, 1H), 7.89 (dd, 1H), 7.82 (dd,1H), 7.64-7.57 (m, 1H), 7.51-7.44 (m, 2H), 7.42-7.33 (m, 1H), 2.44 (s,3H).

LC/MS (Method 1, ESIpos): R_(t)=1.09 min, m/z=497/499 [M+H]⁺.

Example 454-({[6-Bromo-2-(2-fluorophenyl)-3-methylquinolin-4-yl]carbonyl}amino)-3-fluorobenzoicAcid

To a solution of 95 mg (0.19 mmol) of the compound from example 70A in 3ml of THF and 0.6 ml of methanol was added, at RT, 0.94 ml (0.94 mmol)of 1 M sodium hydroxide solution, and the mixture was stirred underreflux for 3 h. After cooling to RT, the organic solvent was removed bydistillation, and 0.07 ml (0.94 mmol) of trifluoroacetic acid was addedto the aqueous phase that remained. The solids formed were filtered off,washed twice with 1 ml of water and dried under reduced pressure. 83 mg(86% of theory, 96% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=13.25 (br. s, 1H), 11.14 (s, 1H), 8.19(t, 1H), 8.06 (d, 1H), 8.02 (d, 1H), 7.96 (dd, 1H), 7.89 (dd, 1H), 7.82(dd, 1H), 7.65-7.50 (m, 2H), 7.45-7.37 (m, 2H), 2.32 (s, 3H).

LC/MS (Method 3, ESIpos): R_(t)=1.34 min, m/z=497/499 [M+H]⁺.

Example 464-({[6-Bromo-3-methyl-2-(pyridin-4-yl)quinolin-4-yl]carbonyl}amino)-3-fluorobenzoicAcid

A mixture of 90 mg (0.18 mmol) of the compound from example 71A in 1 ml(1 mmol) of 1 M sodium hydroxide solution, 1 ml of methanol and 1 ml ofTHF was stirred at RT overnight. Subsequently, the mixture was adjustedto pH 7 by adding a few drops of 1 M hydrochloric acid and the solventwas removed under reduced pressure. The residue was purified by means ofpreparative RP-HPLC (eluent: acetonitrile/10 mM aq. ammonium carbonategradient). 55 mg (63% of theory) of the title compound were obtained.

¹H-NMR (300 MHz, DMSO-d₆): [ppm]=8.79 (d, 2H), 8.14 (m, 2H), 8.05 (d,1H), 7.92 (m, 2H), 7.82 (m, 1H), 7.72 (m, 2H), 2.55 (s, 3H).

LC/MS (Method 4, ESIpos): R_(t)=1.36 min, m/z=479/481 [M+H]+.

Example 476-Bromo-N-(4-carbamoylphenyl)-3-methyl-2-phenylquinoline-4-carboxamide

To 208 mg (0.43 mmol) of the compound from example 35A were graduallyadded 3.5 ml (30 mmol) of ammonia solution (33% in water), and themixture was stirred at RT for 1 h. Subsequently, the mixture was dilutedwith water, and the solids formed were filtered off, washed twice withwater and dried under air. The crude product was purified by preparativeHPLC (Method 5). The combined product-containing fractions wereconcentrated, the residue was taken up in a mixture of dichloromethaneand methanol, and the mixture was concentrated again. After the residuehad been dried under reduced pressure, 113 mg (57% of theory, 100%purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=11.10 (s, 1H), 8.05 (d, 1H), 7.97-7.89(m, 5H), 7.84 (d, 2H), 7.66-7.60 (m, 2H), 7.59-7.47 (m, 3H), 7.31 (br.s, 1H), 2.41 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=0.92 min, m/z=460/462 [M+H]⁺.

Example 486-Bromo-N-(4-carbamoyl-2-fluorophenyl)-3-methyl-2-phenylquinoline-4-carboxamide

To 260 mg (0.52 mmol) of the compound from example 40A were graduallyadded 4.0 ml (33.9 mmol) of ammonia solution (33% in water), and themixture was stirred at RT for 30 min. Subsequently, the solids formedwere filtered off, washed twice with water and dried under air. Thecrude product was purified by preparative HPLC (Method 5). The combinedproduct-containing fractions were concentrated, the residue was taken upin a mixture of dichloromethane and methanol, and the mixture wasconcentrated again. After the residue had been dried under reducedpressure, 181 mg (73% of theory, 100% purity) of the title compound wereobtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=10.96 (s, 1H), 8.12-8.02 (m, 3H), 8.00(d, 1H), 7.94 (dd, 1H), 7.87-7.80 (m, 2H), 7.66-7.61 (m, 2H), 7.60-7.48(m, 4H), 2.44 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=0.98 min, m/z=478/480 [M+H]⁺.

Example 494-{[(6-Bromo-3-methyl-1-oxido-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoicAcid

To a suspension of 100 mg (0.21 mmol) of the compound from example 7 in3 ml of dichloromethane were added, at RT, 113 mg (0.46 mmol, content of70%, remainder water) of 3-chloroperbenzoic acid, suspended in 1 ml ofdichloromethane. The mixture was stirred at RT for 2 h. Subsequently,0.5 ml of THF was added, and the mixture was left to stand at RT for 3days. Thereafter, another 113 mg (0.46 mmol, content of 70%) of3-chloroperbenzoic acid, suspended in 1 ml of dichloromethane, wereadded, and the mixture was stirred at RT for a further day.Subsequently, a further 57 mg (0.23 mmol, content of 70%) of3-chloroperbenzoic acid, suspended in 0.5 ml of dichloromethane, wereadded, and the mixture was stirred at RT for another day. The mixturewas then admixed with 20 ml each of saturated aqueous sodiumhydrogencarbonate solution and dichloromethane, the phases wereseparated and then the aqueous phase was extracted once with 20 ml ofdichloromethane. The aqueous phase was adjusted to pH 1 by addition ofconcentrated hydrochloric acid and extracted twice more with 30 ml eachtime of dichloromethane. The combined organic phases were dried oversodium sulfate, filtered and concentrated. The residue was taken up inDMSO and purified by means of preparative HPLC (method 12). In this way,67 mg (65% of theory, 100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.24 (br. s, 1H), 10.98 (s, 1H),8.51 (d, 1H), 8.23 (t, 1H), 8.07 (d, 1H), 7.99 (dd, 1H), 7.88 (dd, 1H),7.80 (dd, 1H), 7.63-7.48 (m, 3H), 7.43 (d, 2H), 2.16 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=0.87 min, m/z=495/497 [M+H]⁺.

Example 50 Sodium4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoate

Method A:

50 mg (0.10 mmol) of the compound from Example 7 were dissolved in 1.5ml of THF, and 1 M sodium hydroxide solution was added dropwise until pH8 was attained. The mixture was then concentrated to dryness on a rotaryevaporator. The residue was dissolved in a little acetonitrile andmethanol, and lyophilized overnight. 50 mg (95% of theory, 99% purity)of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=10.73 (s, 1H), 8.03-8.01 (m, 2H),7.93-7.91 (d, 1H), 7.71 (s, 2H), 7.66-7.62 (m, 3H), 7.57-7.50 (m, 3H),2.44 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.07 min, m/z=479/481 [M+H]⁺.

Method B:

To 2.0 g (4.18 mmol) of the compound from example 7 were added 100 ml of1,4-dioxane, and the mixture was heated briefly to boiling. To the hotsolution was added a solution of 167 mg (4.18 mmol) of sodium hydroxidein 20 ml of water. After cooling to RT, the mixture was left to stand atRT under air until the solvent had evaporated. After decanting, 2.3 g ofthe title compound were obtained (quant., 100% purity, still containswater).

Example 514-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoicAcid L-Arginine Salt

To 1.1 g (2.30 mmol) of the compound from example 7 were added 200 ml ofmethanol and 5 ml of DMF, and the mixture was heated briefly to boiling.To the hot solution was added a solution of 401 mg (2.30 mmol) ofL-(+)-arginine in 30 ml of water. After cooling to RT, the mixture wasleft to stand at RT under air until the solvent had evaporated. Theremaining residue was suspended in 40 ml of water and stirred at RT forone day. Thereafter, the suspension was filtered and the solids weredried at RT under air. 1.0 g (73% of theory, 100% purity) of the titlecompound was obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.76 (br. s, 1H), 8.04 (d, 1H), 8.00(d, 1H), 8.0-7.7 (br. m, ˜2H), 7.93 (dd, 1H), 7.89-7.82 (m, 1H), 7.77(dd, 1H), 7.69 (dd, 1H), 7.65-7.60 (m, 2H), 7.55 (d, 3H), 3.30-3.03 (m,2H, partially hidden), 2.44 (s, 3H), 1.81-1.53 (m, 4H).

LC/MS (Method 1, ESIpos): R_(t)=1.08 min, m/z=479/481 [M+H]⁺.

Example 524-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-[(methoxymethyl)sulfanyl]benzoicAcid

To a solution of 50 mg (0.09 mmol) of the compound from example 72A in1.5 ml of THF and 0.4 ml of methanol was added, at RT, 0.46 ml (0.46mmol) of 1 M sodium hydroxide solution, and the mixture was stirredunder reflux for 1 h. After cooling to RT, the mixture was admixed with0.035 ml (0.46 mmol) of trifluoroacetic acid and purified by means ofpreparative HPLC (method 18). After the solvent had been removed, theresidue was taken up in a dichloromethane/methanol mixture and thesolution was concentrated again. After the residue had been dried underreduced pressure, 42 mg (87% of theory, 100% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.14 (br. s, 1H), 10.75 (s, 1H),8.25 (dd, 2H), 8.04 (d, 1H), 7.97-7.89 (m, 2H), 7.78 (d, 1H), 7.66-7.61(m, 2H), 7.60-7.49 (m, 3H), 5.09 (s, 2H), 3.34 (s, 3H, hidden), 2.50 (s,3H, hidden).

LC/MS (Method 1, ESIpos): R_(t)=1.12 min, m/z=537/539 [M+H]⁺.

Example 534-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-[(trifluoromethyl)sulfonyl]benzoicAcid

To a solution of 45 mg (0.07 mmol) of the compound from example 75A in1.2 ml of THF and 0.3 ml of methanol was added, at RT, 0.37 ml (0.37mmol) of 1 M sodium hydroxide solution, and the mixture was stirredunder reflux for 2 h. After cooling to RT, the mixture was admixed with0.029 ml (0.37 mmol) of trifluoroacetic acid and purified by means ofpreparative HPLC (method 18). After the solvent had been removed, theresidue was taken up in a dichloromethane/methanol mixture and thesolution was concentrated again. After the residue had been dried underreduced pressure, 41 mg (94% of theory, 100% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.91 (br. s, 1H), 11.01 (s, 1H),8.60 (dd, 1H), 8.58-8.55 (m, 1H), 8.37 (d, 1H), 8.07-8.04 (m, 2H), 7.95(dd, 1H), 7.66-7.61 (m, 2H), 7.60-7.50 (m, 3H), 2.48 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.25 min, m/z=593/595 [M+H]+.

Example 544-{[(6-Bromo-3-methyl-1-oxido-2-phenylquinolin-4-yl)carbonyl]amino}-3-[(trifluoromethyl)sulfanyl]benzoicAcid

To a solution of 43 mg (0.07 mmol) of the compound from example 76A in1.5 ml of THF and 0.3 ml of methanol was added, at RT, 0.37 ml (0.37mmol) of 1 M sodium hydroxide solution, and the mixture was stirredunder reflux for 1 h. After cooling to RT, the mixture was admixed with0.028 ml (0.37 mmol) of trifluoroacetic acid and purified by means ofpreparative HPLC (method 5). After the solvent had been removed, theresidue was taken up in dichloromethane and the solution wasconcentrated again. After the residue had been dried under reducedpressure, 33 mg (78% of theory, 100% purity) of the title compound wereobtained.

¹H-NMR (500 MHz, DMSO-d₆): δ [ppm]=13.45 (br. s, 1H), 11.27 (s, 1H),8.53 (d, 1H), 8.33 (s, 1H), 8.25-8.21 (m, 2H), 8.01 (dd, 1H), 7.93 (d,1H), 7.62-7.57 (m, 2H), 7.56-7.50 (m, 1H), 7.45 (d, 2H), 2.19 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.00 min, m/z=577/579 [M+H]⁺.

Example 554-{[(6-Bromo-5-chloro-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoicAcid

To a solution of 285 mg (0.02 mmol, 4% purity) of the compound fromexample 79A in 7 ml of THF and 1.5 ml of methanol were added, at RT,0.09 ml (0.09 mmol) of 1 M sodium hydroxide solution, and the mixturewas stirred under reflux for 2 h. After cooling to RT, the mixture wasadmixed with 0.008 ml (0.11 mmol) of trifluoroacetic acid and left tostand at RT for about 80 h. Thereafter, the precipitate formed wasfiltered off and washed twice with 0.5 ml of THF. The precipitate newlyformed in the filtrate was likewise filtered off. The filtrate wasconcentrated, and the residue obtained was prepurified by means ofpreparative HPLC (method 19). The product thus obtained was purifiedonce more by means of preparative HPLC [column: Sunfire C18, 5 μm, 100mm×30 mm; flow rate: 75 ml/min; detection: 210 nm; injection volume: 2.0ml; temperature: 40° C.; eluent: water/acetonitrile/(acetonitrile/2%formic acid in water 80:20); gradient: 70:10:20-5:90:5, 10 min]. In thisway, 6.1 mg (55% of theory, 100% purity) of the title compound wereobtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.16 (br. s, 1H), 10.99 (s, 1H),8.33 (t, 1H), 8.13 (d, 1H), 8.02 (d, 1H), 7.88 (dd, 1H), 7.77 (dd, 1H),7.66-7.61 (m, 2H), 7.60-7.53 (m, 3H), 2.44 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.10 min, m/z=513/515 [M+H]⁺.

Example 566-Bromo-N-[2-fluoro-4-(methylcarbamoyl)phenyl]-3-methyl-2-phenylquinoline-4-carboxamide

To 298 mg (0.60 mmol) of the compound from example 40A in 3 ml of THFwere gradually added, at 0° C., 1.90 ml (3.80 mmol) of a 2 M solution ofmethylamine in THF, and the mixture was stirred at RT for 2 h.Subsequently, a further 3 ml of THF and 1 ml (1.90 mmol) of themethylamine solution were added, and the mixture was heated to 70° C. ina microwave apparatus for 30 min. After cooling to RT, another 1 ml(1.90 mmol) of the methylamine solution was added, and the mixture washeated in the microwave at 100° C. for a further 15 min. After coolingto RT, the mixture was admixed with saturated sodium chloride solution,water and 1 M hydrochloric acid, and extracted twice with ethyl acetate.The combined organic phases were washed once with 1 M sodium hydroxidesolution, dried over magnesium sulfate and concentrated. The residue waspurified by means of preparative HPLC (method 12). 43 mg (15% of theory,100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.96 (s, 1H), 8.55 (q, 1H), 8.09 (t,1H), 8.04 (d, 1H), 8.00 (d, 1H), 7.94 (dd, 1H), 7.82-7.76 (m, 2H),7.65-7.61 (m, 2H), 7.59-7.50 (m, 3H), 2.81 (d, 3H), 2.44 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.00 min, m/z=492/494 [M+H]⁺.

Example 574-({[6-Bromo-2-phenyl-3-(trifluoromethyl)quinolin-4-yl]carbonyl}amino)-3-fluorobenzoicAcid

To a solution of 4.5 mg (0.008 mmol) of the compound from example 81A in1 ml of THF and 0.5 ml of methanol was added, at RT, 0.03 ml (0.03 mmol)of 1 M sodium hydroxide solution, and the mixture was stirred underreflux for 14 h. After cooling to RT, the mixture was admixed with 0.003ml (0.035 mmol) of trifluoroacetic acid and concentrated. The residuewas purified by means of preparative HPLC (column: Phenomenex Luna C18,5 μm, 100 mm×21.2 mm; flow rate: 25 ml/min; eluent: water with 1% formicacid/acetonitrile; gradient: 95:5→5:95, 16 min). In this way, 4.5 mg(92% of theory, 90% purity) of the title compound were obtained. Alsoisolated as a secondary component was 0.5 mg (9% of theory, 92% purity)of the compound listed as example 62 (see therein for analysis).

¹H-NMR (500 MHz, DMSO-d₆): δ [ppm]=11.27 (s, 1H), 8.28-8.10 (m, 4H),7.91 (dd, 1H), 7.83 (dd, 1H), 7.56-7.54 (m, 5H).

LC/MS (Method 23, ESIpos): R_(t)=3.54 min, m/z=533/535 [M+H]⁺.

Example 584-{[(6-Bromo-3,8-dimethyl-2-phenylquinolin-4-yl)carbonyl]amino}benzoicAcid

To a solution of 42 mg (0.08 mmol, 96% purity) of methyl4-{[(6-bromo-3,8-dimethyl-2-phenylquinolin-4-yl)carbonyl]amino}benzoate(commercially available) in 1.5 ml of THF and 0.3 ml of methanol wasadded, at RT, 0.4 ml (0.4 mmol) of 1 M sodium hydroxide solution, andthe mixture was stirred under reflux for 1 h. After cooling to RT, themixture was admixed with 0.03 ml (0.4 mmol) of trifluoroacetic acid andpurified by means of preparative HPLC (method 5). In this way, 30 mg(78% of theory, 100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.83 (br. s, 1H), 11.16 (s, 1H),8.00 (d, 2H), 7.89 (d, 2H), 7.86-7.84 (m, 1H), 7.73 (d, 1H), 7.70-7.64(m, 2H), 7.60-7.49 (m, 3H), 2.73 (s, 3H), 2.42 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.23 min, m/z=475/477 [M+H]⁺.

Example 594-{[(6-Chloro-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoicAcid

To a solution of 60 mg (0.13 mmol) of the compound from example 82A in2.7 ml of THF and 0.5 ml of methanol was added, at RT, 0.39 ml (0.39mmol) of 1 M sodium hydroxide solution, and the mixture was stirredunder reflux for 1 h. After cooling to RT, the mixture was admixed with0.045 ml (0.59 mmol) of trifluoroacetic acid, diluted with 2 ml of DMSOand then purified by means of preparative HPLC (method 18). 51 mg (88%of theory, 100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.22 (br. s, 1H), 11.06 (s, 1H),8.22 (t, 1H), 8.15-8.09 (m, 1H), 7.89 (dd, 1H), 7.86-7.78 (m, 3H),7.66-7.60 (m, 2H), 7.59-7.49 (m, 3H), 2.43 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.06 min, m/z=435 [M+H]⁺.

Example 604-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-[(methoxymethyl)sulfonyl]benzoicAcid

To a solution of 70 mg (0.12 mmol) of the compound from example 83A in2.6 ml of THF and 0.5 ml of methanol was added, at RT, 0.60 ml (0.60mmol) of 1 M sodium hydroxide solution, and the mixture was stirredunder reflux for 1 h. After cooling to RT, the mixture was admixed with0.047 ml (0.61 mmol) of trifluoroacetic acid and purified by means ofpreparative HPLC (method 18). 64 mg (91% of theory, 98% purity) of thetitle compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.50 (br. s, 1H), 10.62 (s, 1H),8.49 (d, 1H), 8.46-8.37 (m, 2H), 8.21 (d, 1H), 8.05 (d, 1H), 7.95 (dd,1H), 7.67-7.61 (m, 2H), 7.59-7.50 (m, 3H), 5.02 (s, 2H), 3.42 (s, 3H),2.49 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.15 min, m/z=569/571 [M+H]⁺.

Example 614-{[(6-tert-Butyl-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoicAcid

To a solution of 80 mg (0.17 mmol) of the compound from example 85A in3.5 ml of THF and 0.7 ml of methanol was added, at RT, 0.86 ml (0.86mmol) of 1 M sodium hydroxide solution, and the mixture was stirredunder reflux for 1 h. After cooling to RT, the mixture was admixed with0.066 ml (0.86 mmol) of trifluoroacetic acid and purified by means ofpreparative HPLC (method 5). 61 mg (77% of theory, 98% purity) of thetitle compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.24 (br. s, 1H), 11.01 (s, 1H),8.07-8.00 (m, 2H), 7.94 (dd, 1H), 7.89 (d, 1H), 7.83 (dd, 1H), 7.77 (d,1H), 7.64-7.59 (m, 2H), 7.59-7.48 (m, 3H), 2.42 (s, 3H), 1.38 (s, 9H).

LC/MS (Method 1, ESIpos): R_(t)=1.09 min, m/z=457 [M+H]⁺.

Example 623-Bromo-4-({[6-bromo-2-phenyl-3-(trifluoromethyl)quinolin-4-yl]carbonyl}amino)-5-fluorobenzoicAcid

The title compound was obtained as a secondary component in thepreparation and purification of the compound from example 57 (fordescription see therein).

¹H-NMR (500 MHz, DMSO-d₆): δ [ppm]=11.28 (s, 1H), 8.49 (d, 1H), 8.23(dd, 1H), 8.18 (d, 1H), 8.13-8.10 (m, 1H), 7.94 (dd, 1H), 7.57-7.52 (m,5H).

LC/MS (Method 1, ESIpos): R_(t)=1.14 min, m/z=611/613/615 [M+H]⁺.

Example 633-Fluoro-4-({[3-methyl-6-(pentafluoro-λ⁶-sulfanyl)-2-phenylquinolin-4-yl]carbonyl}amino)benzoicAcid

110 mg (0.20 mmol) of the compound from example 90A were dissolved in 4ml of a THF/methanol mixture (5:1), and 1.02 ml (1.02 mmol) of a 1 Msolution of lithium hydroxide in water were added. The reaction mixturewas stirred at 50° C. for 3 h. Subsequently, the mixture was cooled toRT, adjusted to pH 1-2 with 4 M hydrochloric acid and, without furtherworkup, purified by means of preparative HPLC (method 6). The productfractions were concentrated and the residue was dried under reducedpressure. 85 mg (79% of theory, 100% purity) of the title compound wereobtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.28 (br. s, 1H), 11.14 (s, 1H),8.35-8.22 (m, 3H), 8.09 (t, 1H), 7.90 (dd, 1H), 7.84 (dd, 1H), 7.73-7.63(m, 2H), 7.63-7.50 (m, 3H), 2.49 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.14 min, m/z=527 [M+H]⁺.

Example 644-({[6-(Difluoromethyl)-3-methyl-2-phenylquinolin-4-yl]carbonyl}amino)-3-fluorobenzoicAcid

55 mg (0.18 mmol) of the compound from example 94A were dissolved in 2ml of DMF under argon, and 57 mg (0.35 mmol) of N,N′-carbonyldiimidazolewere added at RT. The reaction mixture was stirred at 60° C. overnight,and then water and ethyl acetate added. The phases were separated, andthe aqueous phase was extracted three times with ethyl acetate. Thecombined organic phases were dried over sodium sulfate and concentrated.The residue was dissolved in 1.55 ml of dichloromethane, and 29.8 mg(0.26 mmol) of methyl 4-amino-3-fluorobenzoate were added. Subsequently,0.44 ml (0.44 mmol) of a 1 M solution of potassium tert-butoxide in THFwas added. The reaction mixture was stirred at RT overnight, and then0.88 ml (0.88 mmol) of a 1 M solution of lithium hydroxide in water wasadded. The reaction mixture was then stirred at 50° C. for 3 h. Themixture was then cooled to RT, adjusted to pH 1-2 with 4 M hydrochloricacid and, without further workup, purified by means of preparative HPLC(method 6). The product fractions were concentrated and the residue wasdried under reduced pressure. In this way, 20 mg (23% of theory, 90%purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.24 (br. s, 1H), 11.08 (s, 1H),8.35-8.17 (m, 2H), 8.09 (s, 1H), 7.98-7.87 (m, 2H), 7.82 (dd, 1H),7.67-7.62 (m, 2H), 7.60-7.51 (m, 3H), 7.31 (t, 1H), 2.45 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.03 min, m/z=451 [M+H]⁺.

Example 654-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2,3-difluorobenzoicAcid

105 mg (0.21 mmol) of the compound from example 95A were dissolved in 5ml of a THF/methanol mixture (5:1), and 1.03 ml (1.03 mmol) of a 1 Msolution of lithium hydroxide in water were added. The reaction mixturewas stirred at 50° C. for 3 h, then cooled to RT and adjusted to pH 1-2with 4 M hydrochloric acid. Subsequently, the mixture, without furtherworkup, was purified by means of preparative HPLC (method 6). Theproduct fractions were concentrated, and the residue was lyophilized andthen recrystallized from water. Drying under reduced pressure gave 69 mg(68% of theory, purity 100%) of the title compound.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.51 (br. s, 1H), 11.24 (s, 1H),8.08-8.03 (m, 1H), 8.03-7.96 (m, 2H), 7.93 (dd, 1H), 7.85-7.74 (m, 1H),7.66-7.60 (m, 2H), 7.60-7.48 (m, 3H), 2.43 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.03 min, m/z=497/499 [M+H]⁺.

Example 664-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2,5-difluorobenzoicAcid

99 mg (0.17 mmol, 85% purity) of the compound from example 96A weredissolved in 5 ml of a THF/methanol mixture (5:1), and 0.82 ml (0.82mmol) of a 1 M solution of lithium hydroxide in water were added. Thereaction mixture was stirred at 50° C. for 3 h, then cooled to RT andadjusted to pH 1-2 with 4 M hydrochloric acid. Subsequently, themixture, without further workup, was purified by means of preparativeHPLC (method 6). The product fractions were concentrated and the residuewas dried under reduced pressure. 81 mg (99% of theory, >99% purity) ofthe title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.47 (br. s, 1H), 11.23 (s, 1H),8.25 (dd, 1H), 8.04 (d, 1H), 8.01 (d, 1H), 7.93 (dd, 1H), 7.77 (dd, 1H),7.66-7.60 (m, 2H), 7.60-7.48 (m, 3H), 2.41 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.07 min, m/z=497/499 [M+H]⁺.

Example 676-Bromo-N-(2-fluoro-4-{[(trifluoromethyl)sulfonyl]carbamoyl}phenyl)-3-methyl-2-phenylquinoline-4-carboxamide

To a suspension of 20 mg (0.50 mmol) of sodium hydride (60% in mineraloil) in 2.5 ml of THF were added 75 mg (0.50 mmol) oftrifluoromethanesulfonamide, and the mixture was stirred at RT for 30min. Subsequently, 124 mg (0.25 mmol) of the compound from example 40Awere added, and the mixture was stirred at RT for a further 30 min. Thenthe mixture was concentrated. The residue was taken up in DMSO andpurified by means of preparative HPLC (method 18). Theproduct-containing fractions were concentrated, and the residue wastaken up in a mixture of dichloromethane and methanol, concentratedagain and then dried under reduced pressure. 77 mg (50% of theory, 100%purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.90 (s, 1H), 8.07-7.98 (m, 3H),7.95 (dd, 1H), 7.85 (dd, 1H), 7.75 (dd, 1H), 7.66-7.61 (m, 2H),7.60-7.50 (m, 3H), 2.44 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.10 min, m/z=610/612 [M+H]⁺.

Example 686-Bromo-N-{4-[(dimethylsulfamoyl)carbamoyl]-2-fluorophenyl}-3-methyl-2-phenylquinoline-4-carboxamide

To a suspension of 20 mg (0.50 mmol) of sodium hydride (60% in mineraloil) in 2.5 ml of THF were added 62 mg (0.50 mmol) ofN,N-dimethylsulfonamide, and the mixture was stirred at RT for 30 min.Subsequently, 1 ml of DMF was added and the mixture was stirred at 50°C. for 2 h. After cooling to RT, 124 mg (0.25 mmol) of the compound fromexample 40A were added, and the mixture was stirred at RT for a further30 min. Then the mixture was concentrated. The residue was taken up inDMSO and purified by means of preparative HPLC (method 18). Theproduct-containing fractions were concentrated, and the residue wastaken up in a mixture of dichloromethane and methanol, concentratedagain and then dried under reduced pressure. 40 mg (27% of theory, 100%purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.92 (s, 1H), 11.08 (s, 1H), 8.22(t, 1H), 8.05 (d, 1H), 7.99 (d, 1H), 7.95 (d, 1H), 7.94-7.87 (m, 2H),7.66-7.61 (m, 2H), 7.59-7.48 (m, 3H), 2.91 (s, 6H), 2.43 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.11 min, m/z=585/587 [M+H]⁺.

Example 69 Potassium4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoate

To 1.10 g (2.30 mmol) of the compound from example 7 were added 200 mlof methanol and 5 ml of DMF, and the mixture was heated briefly toboiling. To the hot solution was added a solution of 129 mg (2.30 mmol)of potassium hydroxide in 30 ml of water. After cooling to RT, themixture was left to stand at RT under air until the solvent hadevaporated. A portion of the residue was subjected to heat treatment at200° C. for 1-1.5 h. After cooling to RT and decanting, 0.50 g (42% oftheory, 100% purity) of the title compound was obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.72 (br. s, 1H), 8.05-8.00 (m, 2H),7.95-7.90 (m, 1H), 7.76-7.68 (m, 2H), 7.67-7.60 (m, 3H), 7.59-7.49 (m,3H), 2.45 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.05 min, m/z=479/481 [M+H]⁺.

Example 704-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoicAcid L-Lysine Salt

To 2.0 g (4.18 mmol) of the compound from example 7 were added 100 ml of1,4-dioxane, and the mixture was heated briefly to boiling. To the hotsolution was added a solution of 610 mg (4.18 mmol) of L-lysine in 20 mlof water. After cooling to RT, the mixture was left to stand at RT underair until the solvent had evaporated. The residue was suspended in 20 mlof an ethanol/water mixture (1:1) and stirred at RT for one week.Subsequently, the solids were filtered off and dried under air at RT.2.2 g of the title compound were obtained (84% of theory, 100% purity,still contains solvent).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.70 (br. s, 1H), 8.03 (d, 1H), 8.00(d, 1H), 7.93 (dd, 1H), 7.82 (t, 1H), 7.75 (dd, 1H), 7.68 (dd, 1H),7.65-7.60 (m, 2H), 7.59-7.49 (m, 3H), 3.16 (t, 1H), 2.75 (t, 2H), 2.44(s, 3H), 1.79-1.29 (m, 6H).

LC/MS (Method 1, ESIpos): R_(t)=1.05 min, m/z=479/481 [M+H]⁺.

Example 71 2-Hydroxy-N,N,N-trimethylethanaminium4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoate

To 2.0 g (4.18 mmol) of the compound from example 7 were added 100 ml of1,4-dioxane, and the mixture was heated briefly to boiling. To the hotsolution was added a mixture of 1.23 g (5.09 mmol) of a 50% by weightaqueous solution of 2-hydroxy-N,N,N-trimethylethanaminium hydroxide(choline hydroxide) and 20 ml of water. After cooling to RT, the mixturewas left to stand at RT under air until the solvent had evaporated. 2.5g of the title compound were obtained (quant., 100% purity, stillcontains water).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.62 (br. s, 1H), 8.07-7.98 (m, 2H),7.96-7.87 (m, 1H), 7.74-7.65 (m, 2H), 7.65-7.59 (m, 3H), 7.59-7.47 (m,3H), 3.87-3.82 (m, 2H), 3.43-3.38 (m, 2H), 3.11 (s, 9H), 2.44 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.06 min, m/z=479/481 [M+H]⁺.

Example 724-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoicacid 2-amino-2-(hydroxymethyl)propane-1,3-diol Salt

To 2.0 g (4.18 mmol) of the compound from example 7 were added 100 ml of1,4-dioxane, and the mixture was heated briefly to boiling. To the hotsolution was added a solution of 507 mg (4.18 mmol) of2-amino-2-(hydroxymethyl)propane-1,3-diol (TRIS) in 20 ml of water.After cooling to RT, the mixture was left to stand at RT under air untilthe solvent had evaporated. After decanting, 2.5 g of the title compoundwere obtained (quant., 100% purity, still contains water).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.89 (br. s, 1H), 8.04 (d, 1H), 8.01(d, 1H), 7.97-7.90 (m, 2H), 7.80 (dd, 1H), 7.72 (dd, 1H), 7.66-7.60 (m,2H), 7.60-7.49 (m, 3H), 3.44 (s, 6H), 2.45 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.07 min, m/z=479/481 [M+H]⁺.

Example 734-{[(6-Bromo-3-fluoro-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoicAcid

To a solution of 45 mg (0.06 mmol, 69% purity) of the compound fromexample 98A in 1.0 ml of THF and 0.2 ml of methanol was added, at RT,0.31 ml (0.31 mmol) of 1 M sodium hydroxide solution, and the mixturewas stirred under reflux for 1.5 h. After cooling to RT, 0.03 ml (0.37mmol) of trifluoroacetic acid was added. Subsequently, the mixture waspurified directly by means of preparative HPLC (method 18). 5 mg (16% oftheory, 94% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=13.22 (br. s, 1H), 11.21 (s, 1H), 8.33(t, 1H), 8.17-8.12 (m, 2H), 8.09-8.04 (m, 2H), 8.00 (dd, 1H), 7.89 (dd,1H), 7.81 (dd, 1H), 7.65-7.57 (m, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.14 min, m/z=483/485 [M+H]⁺.

Example 744-{[(6-Bromo-3-methoxy-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoicAcid

The title compound was obtained as a further product of the reactiondescribed in example 73. In the purification of the reaction mixture bypreparative HPLC by method 18 (see example 73), a further productfraction had been obtained, which was purified further by anotherpreparative HPLC [column: Kinetix C18, 5 μm, 100×21.2 mm; flow rate: 60ml/min; detection: 210 nm; injection volume: 1.0 ml; temperature: 40°C.; eluent: gradient 95% water/0% acetonitrile/5% (acetonitrile/water80:20+2% formic acid)→30% water/65% acetonitrile/5% (acetonitrile/water80:20+2% formic acid); run time: 10.8 min]. In this way, 9 mg (29% oftheory, 100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=11.03 (s, 1H), 8.23 (t, 1H), 8.07 (d,1H), 8.02-7.98 (m, 3H), 7.91 (dd, 1H), 7.88 (d, 1H), 7.80 (d, 1H),7.61-7.53 (m, 3H), 3.65 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.08 min, m/z=495/497 [M+H]⁺.

Example 754-{[(3-Chloro-6-iodo-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoicAcid

To a solution of 46 mg (0.07 mmol, 90% purity) of the compound fromexample 101A in 2.3 ml of THF and 0.5 ml of methanol was added, at RT,0.44 ml (0.44 mmol) of 1 M sodium hydroxide solution, and the mixturewas stirred at RT for 20 h. Subsequently, the mixture was acidified topH 3 with trifluoroacetic acid and purified by means of preparative HPLC(method 18). 32 mg (77% of theory, 98% purity) of the title compoundwere obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=13.24 (br. s, 1H), 11.20 (s, 1H), 8.31(t, 1H), 8.21 (d, 1H), 8.17 (dd, 1H), 7.94 (d, 1H), 7.90 (dd, 1H), 7.82(dd, 1H), 7.78-7.73 (m, 2H), 7.61-7.52 (m, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.11 min, m/z=547 [M+H]⁺.

Example 764-{[(6-Bromo-3-chloro-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoicAcid

To a solution of 45 mg (0.07 mmol, 85% purity) of the compound fromexample 104A in 2.3 ml of THF and 0.5 ml of methanol was added, at RT,0.44 ml (0.44 mmol) of 1 M sodium hydroxide solution, and the mixturewas stirred at RT for 20 h. Subsequently, the mixture was acidified topH 3 with trifluoroacetic acid and prepurified by means of preparativeHPLC (method 18). The product thus obtained was dissolved in 10 ml of anacetonitrile/methanol/DMSO/formic acid mixture while heating andpurified further by another preparative HPLC [column: Kinetix C18, 5 μm,100×21.2 mm; flow rate: 25 ml/min; detection: 210 nm; injection volume:2.75 ml; temperature: 35° C.; eluent: gradient 50% water/45%acetonitrile/5% formic acid (1% in water)→20% water/75% acetonitrile/5%formic acid (1% in water); run time: 6.0 min]. In this way, 22 mg (56%of theory, 95% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.24 (br. s, 1H), 11.21 (s, 1H),8.32 (t, 1H), 8.14-8.09 (m, 1H), 8.07-8.02 (m, 2H), 7.92-7.87 (m, 1H),7.81 (dd, 1H), 7.78-7.73 (m, 2H), 7.61-7.54 (m, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.09 min, m/z=499/501 [M+H]⁺.

Example 774-{[(6-Bromo-3-cyclopropyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoicAcid

To a solution of 33 mg (0.05 mmol, 77% purity) of the compound fromexample 106A in 1.5 ml of THF and 0.3 ml of methanol was added, at RT,0.073 ml (0.073 mmol) of 1 M sodium hydroxide solution, and the mixturewas left to stand at RT for 2 h. Subsequently, the mixture was stirredat 60° C. for 5 h and then left to stand again at RT for 2 days. Afteradding a further 0.15 ml (0.15 mmol) of 1 M sodium hydroxide solution,the mixture was stirred once again at 60° C. for one day. Thereafter,the mixture was acidified to pH 3 with trifluoroacetic acid and purifiedby means of preparative HPLC (method 18). 19 mg (75% of theory, 100%purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=13.24 (br. s, 1H), 11.00 (s, 1H), 8.25(t, 1H), 8.07-8.02 (m, 2H), 7.94 (dd, 1H), 7.90 (dd, 1H), 7.82 (dd, 1H),7.76 (dd, 2H), 7.57-7.46 (m, 3H), 2.46-2.30 (m, 1H), 0.68 (d, 2H), 0.33(d, 2H).

LC/MS (Method 1, ESIpos): R_(t)=1.15 min, m/z=505/507 [M+H]⁺.

Example 784-{[(6-Bromo-3,8-dimethyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoicAcid

To a solution of 649 mg (1.02 mmol, 80% purity) of the compound fromexample 108A in 13 ml of THF and 2.6 ml of methanol was added, at RT,4.3 ml (4.3 mmol) of 1 M sodium hydroxide solution, and the mixture wasstirred under reflux for 1.5 h. After cooling to RT, the mixture wasacidified to pH 3 with trifluoroacetic acid and then purified by meansof preparative HPLC [column: Kinetix C18, 5 μm, 100×21.2 mm; flow rate:60 ml/min; detection: 210 nm; injection volume: 1.0 ml; temperature: 40°C.; eluent: gradient 50% water/30% acetonitrile/20% (acetonitrile/water80:20+2% formic acid)→30% water/65% acetonitrile/5% (acetonitrile/water80:20+2% formic acid); run time: 5.7 min]. 419 mg (83% of theory, 100%purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=13.25 (br. s, 1H), 11.02 (s, 1H), 8.19(t, 1H), 7.89 (dd, 1H), 7.86-7.83 (m, 1H), 7.81 (td, 2H), 7.70-7.64 (m,2H), 7.60-7.49 (m, 3H), 2.73 (s, 3H), 2.45 (s, 3H).

LC/MS (Method 1, ESIpos): R_(t)=1.19 min, m/z=493/495 [M+H]⁺.

B. ASSESSMENT OF PHARMACOLOGICAL EFFICACY

The pharmacological activity of the compounds of the invention can bedemonstrated by in vitro and in vivo studies as known to the personskilled in the art. The application examples which follow describe thebiological action of the compounds of the invention, without restrictingthe invention to these examples.

Abbreviations and Acronyms

-   BSA bovine serum albumin-   CRTH2 chemoattractant receptor-homologous molecule expressed on T    helper type 2 cells-   DMEM Dulbecco's modified Eagle's medium-   DMSO dimethyl sulfoxide-   DP PGD2 receptor-   EC₅₀ half-maximum effective concentration-   em. emission-   EP PGE2 receptor-   ex. excitation-   FCS fetal calf serum-   FP PGF2α receptor-   HEPES 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid-   IC₅₀ half-maximum inhibitory concentration-   IP PGI2 receptor-   MES 2-(N-morpholino)ethanesulfonic acid-   Pen/Strep penicillin/streptomycin-   PGD2 prostaglandin D2-   PGE2 prostaglandin E2-   PGF2α prostaglandin F2α-   PGI2 prostaglandin 12-   TC tissue culture-   TP thromboxane A2 receptor-   Tris tris(hydroxymethyl)aminomethane-   v/v volume to volume ratio (of a solution)-   w/w weight to weight ratio (of a solution)

B-1. In Vitro Test of Inhibition of Human FP Receptor Activity VariantB-1A:

For the characterization of test substances in respect of FP antagonism,PGF2α-induced calcium flux in FP-expressing CHEM1 cells (Millipore,HTS093C) was used.

3000 cells in 25 μl of full medium [DMEM F12, 10% FCS, 1.35 mM sodiumpyruvate, 20 mM HEPES, 4 mM GlutaMAX™, 2% sodium bicarbonate, 1%Pen/Strep, 1% 100× non-essential amino acids] are sown per well of a 384multititer plate (from Greiner, TC plate, black with clear base) andincubated at 37° C./5% CO₂ for 24 hours. Prior to the measurement, themedium is replaced by 30 μl of Fluo-8 AM loading buffer [calcium-freeTyrode (130 mM NaCl, 5 mM KCl, 20 mM HEPES, 1 mM MgCl₂, 4.8 mM NaHCO₃,pH 7.4), 2 mM CaCl₂, 1× SmartBlock (from CANDOR Bioscience GmbH), 4.5 mMProbenecid, 5 μM Fluo-8 AM, 0.016% Pluronic®, 0.04% Brilliant black] andincubated at 37° C./5% CO₂ for 30 minutes. The test substance isprepared in DMSO in various concentrations as a dose-response curve(starting concentration 10 mM, dilution factor 3.16) and prediluted 1:50with calcium-free Tyrode/2 mM CaCl₂. 10 μl of the prediluted substancesolution are added to the Fluo-8-laden cells and incubated at 37° C./5%CO₂ for 10 minutes. The FP receptor is activated by adding 20 μl of 3 nM(final concentration) PGF2α in calcium-free Tyrode/2 mM CaCl₂/0.04%Brilliant black, and the calcium flux is determined by measuring thefluorescence at ex. 470 nm/em. 525 nm in a fluorescence measuringinstrument (FLIPR Tetra®, Molecular Devices) for 120 seconds.

Table 1A below lists the IC₅₀ values from this assay for individualworking examples of the invention (some as mean values from multipleindependent individual determinations):

TABLE 1A FP receptor activity Example no. IC₅₀ [μmol/l] 1 0.166 2 0.1483 0.170 4 0.880 5 0.905 6 0.079 7 0.020 8 0.795 9 0.065 10 0.041 110.053 12 0.022 13 0.150 14 0.617 15 0.045 16 0.278 17 0.060 18 0.335 190.650 20 0.530 21 0.204 22 0.290 23 0.057 24 0.124 25 0.720 26 0.086 270.097 28 0.017 29 0.890 30 0.006 31 0.165 32 0.245 33 0.272 34 0.093 350.290 36 0.078 37 0.039 38 0.265 39 0.190 40 0.560 41 0.025 42 0.033 430.052 44 0.033 45 0.205 46 0.140 47 0.197 48 0.102 49 0.120 50 0.037 510.091 52 0.017 53 0.031 54 0.102 55 0.049 56 0.285 57 0.437 58 0.557 590.203 60 0.027 61 0.131 62 0.301 63 0.246 64 0.362 65 0.105 66 0.282 670.239 68 0.318 69 0.104 70 0.089 71 0.090 72 0.079 74 0.220 75 0.009 760.017 77 0.027 78 0.154

Variant B-1B:

For the characterization of test substances in respect of FP antagonism,the PGF2α-induced calcium flux in recombinant FP-expressing CHO cellswhich additionally express the Ca²⁺ sensor protein GCaMP6 was used.

3000 cells in 25 μl of full medium [DMEM F12, 10% FCS, 1.35 mM sodiumpyruvate, 20 mM HEPES, 4 mM GlutaMAX™, 2% sodium bicarbonate, 1%Pen/Strep, 1% 100× non-essential amino acids] are sown per well of a 384multititer plate (from Greiner, TC plate, black with clear base) andincubated at 37° C., 5% CO₂ for 24 hours. Prior to the measurement, themedium is replaced by 30 μl of buffer [calcium-free Tyrode (130 mM NaCl,5 mM KCl, 20 mM HEPES, 1 mM MgCl₂, 4.8 mM NaHCO₃, pH 7.4), 2 mM CaCl₂,0.01% BSA] and incubated at 37° C., 5% CO₂ for 30 minutes. The testsubstance is prepared in DMSO in various concentrations as adose-response curve (starting concentration 10 mM, dilution factor 3.16)and prediluted 1:50 with calcium-free Tyrode/2 mM CaCl₂/0.01% BSA. 10 μlof the prediluted substance solution are added to the cells andincubated at 37° C., 5% CO₂ for 10 minutes. The FP receptor is activatedby adding 20 μl of 3 nM (final concentration) PGF2α in calcium-freeTyrode/2 mM CaCl₂, and the calcium flux is determined by measuring thefluorescence at ex. 470 nm/em. 525 nm in a fluorescence measuringinstrument (FLIPR Tetra®, MolecularDevices) for 120 seconds.

Table 1B below lists the IC₅₀ values from this assay for individualworking examples of the invention (some as mean values from multipleindependent individual determinations):

TABLE 1B FP receptor activity Example no. IC₅₀ [μmol/l] 7 0.034 50 0.04451 0.038 52 0.006 61 0.079 65 0.060 67 0.134 68 0.182 69 0.059 70 0.05371 0.047 72 0.043 73 0.098

B-2. In Vitro FP Receptor Binding Inhibition Test

For the FP receptor binding test, human recombinant prostanoid FPreceptors, expressed in HEK293 cells, in modified MES buffer, pH 6.0,are used. This test is conducted commercially (at Eurofins Panlabs,catalog #268510). 80 μg of membrane are incubated with 1 nM [³H]-PGF2αat 25° C. for 60 minutes. The amount of membrane protein can vary frombatch to batch and is adjusted if required. Unspecific binding isdetermined in the presence of 1 μM cloprostenol. The membranes arefiltered, washed and then analyzed in order to determine the specificbinding of [³H]-PGF2α. Substances are tested for inhibitory activity ata concentration of 10 μM or in the form of a dose-response curve [lit.:Abramovitz et al., J. Biol. Chem. 1994, 269 (4): 2632].

B-3. In Vitro CRTH2 Receptor Binding Inhibition Test

For this test, human recombinant prostanoid CRTH2 receptors, expressedin CHO-K1 cells, in modified Tris-HCl buffer, pH 7.4, are used. Thistest is conducted commercially (at Eurofins Panlabs, catalog #268030). 4μg of membrane are incubated with 1 nM [³H]-PGD2 at 25° C. for 120minutes. The amount of membrane protein can vary from batch to batch andis adjusted if required. Unspecific binding is determined in thepresence of 1 μM PGD2. The membranes are filtered, washed and thenanalyzed in order to determine the specific binding of [³H]-PGD2.Substances are tested for inhibitory activity at a concentration of 10μM or in the form of a dose-response curve [lit.: Sugimoto et al., J.Pharmacol. Exp. Ther. 2003, 305 (1): 347].

B-4. In Vitro DP Receptor Binding Inhibition Test

For this test, human recombinant prostanoid DP receptors, expressed inChem-1 cells, in modified HEPES buffer, pH 7.4, are used. This test isconducted commercially (at Eurofins Panlabs, catalog #268060). 10 μg ofmembrane are incubated with 2 nM [³H]-PGD2 at 25° C. for 120 minutes.The amount of membrane protein can vary from batch to batch and isadjusted if required. Unspecific binding is determined in the presenceof 1 μM PGD2. The membranes are filtered, washed and then analyzed inorder to determine the specific binding of [³H]-PGD2. Substances aretested for inhibitory activity at a concentration of 10 μM or in theform of a dose-response curve [lit.: Wright et al., Br. J. Pharmacol.1998, 123 (7): 1317; Sharif et al., Br. J. Pharmacol. 2000, 131 (6):1025].

B-5. In Vitro EP1 Receptor Binding Inhibition Test

For this test, human recombinant prostanoid EP1 receptors, expressed inHEK293 cells, in modified MES buffer, pH 6.0, are used. This test isconducted commercially (at Eurofins Panlabs, catalog #268110). 14 μg ofmembrane are incubated with 1 nM [³H]-PGE2 at 25° C. for 60 minutes. Theamount of membrane protein can vary from batch to batch and is adjustedif required. Unspecific binding is determined in the presence of 10 μMPGE2. The membranes are filtered, washed and then analyzed in order todetermine the specific binding of [³H]-PGE2. Substances are tested forinhibitory activity at a concentration of 10 μM or in the form of adose-response curve [lit.: Abramovitz et al., Biochim. Biophys. Acta2000, 1483 (2): 285; Funk et al., J. Biol. Chem. 1993, 268 (35): 26767].

B-6. In Vitro EP2 Receptor Binding Inhibition Test

For this test, human recombinant prostanoid EP2 receptors, expressed inHEK293 cells, in modified MES/KOH buffer, pH 6.0, are used. This test isconducted commercially (at Eurofins Panlabs, catalog #268200). 25 mg/mlof membrane are incubated with 4 nM [³H]-PGE2 at 25° C. for 120 minutes.The amount of membrane protein can vary from batch to batch and isadjusted if required. Unspecific binding is determined in the presenceof 10 μM PGE2. The membranes are filtered, washed and then analyzed inorder to determine the specific binding of [³H]-PGE2. Substances aretested for inhibitory activity at a concentration of 10 μM or in theform of a dose-response curve [lit.: Bastien et al., J. Biol. Chem.1994, 269 (16): 11873; Boie et al., Eur. J. Pharmacol. 1997, 340 (2-3):227].

B-7. In Vitro EP3 Receptor Binding Inhibition Test

For this test, human recombinant prostanoid EP3 receptors, expressed inHEK293 cells, in modified MES buffer, pH 6.0, are used. This test isconducted commercially (at Eurofins Panlabs, catalog #268310). 3 μg ofmembrane are incubated with 0.5 nM [³H]-PGE2 at 25° C. for 120 minutes.The amount of membrane protein can vary from batch to batch and isadjusted if required. Unspecific binding is determined in the presenceof 10 μM PGE2. The membranes are filtered, washed and then analyzed inorder to determine the specific binding of [³H]-PGE2. Substances aretested for inhibitory activity at a concentration of 10 μM or in theform of a dose-response curve [lit.: Schmidt et al., Eur. J. Biochem.1995, 228 (1): 23].

B-8. In Vitro EP4 Receptor Binding Inhibition Test

For this test, human recombinant prostanoid EP4 receptors, expressed inChem-1 cells, in modified MES buffer, pH 6.0, are used. This test isconducted commercially (at Eurofins Panlabs, catalog #268420). 3 μg ofmembrane are incubated with 1 nM [³H]-PGE2 at 25° C. for 120 minutes.The amount of membrane protein can vary from batch to batch and isadjusted if required. Unspecific binding is determined in the presenceof 10 μM PGE2. The membranes are filtered, washed and then analyzed inorder to determine the specific binding of [³H]-PGE2. Substances aretested for inhibitory activity at a concentration of 10 μM or in theform of a dose-response curve [lit.: Davis et al., Br. J. Pharmacol.2000, 130 (8): 1919].

B-9. In Vitro IP Receptor Binding Inhibition Test

For this test, human recombinant prostanoid IP receptors, expressed inHEK293 cells, in modified HEPES buffer, pH 6.0, are used. This test isconducted commercially (at Eurofins Panlabs, catalog #268600). 15 μg ofmembrane are incubated with 5 nM [³H]-iloprost at 25° C. for 60 minutes.The amount of membrane protein can vary from batch to batch and isadjusted if required. Unspecific binding is determined in the presenceof 10 μM iloprost. The membranes are filtered, washed and then analyzedin order to determine the specific binding of [³H]-iloprost. Substancesare tested for inhibitory activity at a concentration of 10 μM or in theform of a dose-response curve [lit.: Armstrong et al., Br. J. Pharmacol.1989, 97 (3): 657; Boie et al., J. Biol. Chem. 1994, 269 (16): 12173].

B-10. In Vitro TP Receptor Binding Inhibition Test

For this test, human recombinant prostanoid TP receptors, expressed inHEK-293 EBNA cells, in modified Tris/HCl buffer, pH 7.4, are used. Thistest is conducted commercially (at Eurofins Panlabs, catalog #285510).18.4 μg of membrane are incubated with 5 nM [³H]-SQ-29 548 at 25° C. for30 minutes. The amount of membrane protein can vary from batch to batchand is adjusted if required. Unspecific binding is determined in thepresence of 1 M SQ-29 548. The membranes are filtered, washed and thenanalyzed in order to determine the specific binding of [³H]-SQ-29 548.Substances are tested for inhibitory activity at a concentration of 10μM or in the form of a dose-response curve [lit.: Saussy Jr. et al., J.Biol. Chem. 1986, 261: 3025; Hedberg et al., J. Pharmacol. Exp. Ther.1988, 245: 786].

B-11. In Vitro Test for DP Agonism and Antagonism

For the characterization of test substances in respect of DP agonism andantagonism, PGD2-induced calcium flux in DP-expressing CHEM1 cells(Millipore, HTS091C) was used: 3000 cells in 25 μl of full medium [DMEM,4.5 g/l glucose, 10% heat-inactivated FCS, 1% 100× non-essential aminoacids, 10 mM HEPES, 0.25 mg/ml Geneticin (G418), 100 U/ml penicillin andstreptomycin] are sown per well of a 384 multititer plate (from Greiner,TC plate, black with clear base) and incubated at 37° C./5% CO₂ for 24hours. Prior to the measurement, the medium is replaced by 30 l ofcalcium dye loading buffer (FLIPR Calcium Assay, Molecular Devices) andincubated at 37° C./5% CO₂ for 60 minutes. The test substance isprepared in DMSO in various concentrations as a dose-response curve(starting concentration 10 mM, dilution factor 3.16) and prediluted 1:50with, for example, calcium-free Tyrode (130 mM NaCl, 5 mM KCl, 20 mMHEPES, 1 mM MgCl₂, 4.8 mM NaHCO₃, pH 7.4)/2 mM CaCl₂. For themeasurement of DP agonism, in a fluorescence measuring instrument (FLIPRTetra®, Molecular Devices), 10 μl of the prediluted substance solutionare added to the calcium dye-laden cells, and the calcium flux isdetermined by measuring the fluorescence at ex. 470 nm/em. 525 nm for120 seconds. Thereafter, the cells are incubated at 37° C./5% CO₂ for 10minutes. For the measurement of DP antagonism, the DP receptor isactivated in the FLIPR Tetra® by adding 20 μl of ˜76 nM (2×EC₅₀, finalconcentration) PGD2 in, for example, calcium-free Tyrode/2 mM CaCl₂, andthe calcium flux is determined by measuring the fluorescence at ex. 470nm/em. 525 nm for 120 seconds [lit.: T. Matsuoka et al. (2000) Science287: 2013-2017; S. Narumiya and G. A. Fitzgerald (2001) J. Clin. Invest.108: 25-30].

B-12. In Vitro Test for EP1 Agonism and Antagonism

For the characterization of test substances in respect of EP 1 agonismand antagonism, PGE2-induced calcium flux in EP1-expressing CHEM1 cells(Millipore, HTS099C) was used: 3000 cells in 25 μl of full medium [DMEM,4.5 g/l glucose, 10% heat-inactivated FCS, 1% 100× non-essential aminoacids, 10 mM HEPES, 0.25 mg/ml Geneticin (G418), 100 U/ml penicillin andstreptomycin] are sown per well of a 384 multititer plate (from Greiner,TC plate, black with clear base) and incubated at 37° C./5% CO₂ for 24hours. Prior to the measurement, the medium is replaced by 30 μl ofcalcium dye loading buffer (FLIPR Calcium Assay, Molecular Devices) andincubated at 37° C./5% CO₂ for 60 minutes. The test substance isprepared in DMSO in various concentrations as a dose-response curve(starting concentration 10 mM, dilution factor 3.16) and prediluted 1:50with, for example, calcium-free Tyrode (130 mM NaCl, 5 mM KCl, 20 mMHEPES, 1 mM MgCl₂, 4.8 mM NaHCO₃, pH 7.4)/2 mM CaCl₂. For themeasurement of EP1 agonism, in a fluorescence measuring instrument(FLIPR Tetra®, Molecular Devices), 10 μl of the prediluted substancesolution are added to the calcium dye-laden cells, and the calcium fluxis determined by measuring the fluorescence at ex. 470 nm/em. 525 nm for120 seconds. Thereafter, the cells are incubated at 37° C./5% CO₂ for 10minutes. For the measurement of EP 1 antagonism, the EP 1 receptor isactivated in the FLIPR Tetra® by adding 20 μl of ˜6 nM (2×EC₅₀, finalconcentration) PGE2 in, for example, calcium-free Tyrode/2 mM CaCl₂, andthe calcium flux is determined by measuring the fluorescence at ex. 470nm/em. 525 nm for 120 seconds [lit.: Y. Matsuoka et al. (2005) Proc.Natl. Acad. Sci. USA 102: 16066-16071; S. Narumiya and G. A. Fitzgerald(2001) J. Clin. Invest. 108: 25-30; K. Watanabe et al. (1999) CancerRes. 59: 5093-5096].

B-13. In Vitro Test for EP2 Agonism and Antagonism

For the characterization of test substances in respect of EP2 agonismand antagonism, PGE2-induced calcium flux in EP2-expressing CHEM9 cells(Millipore, HTS185C) was used: 3000 cells in 25 μl of plating medium[DMEM, 4.5 g/l glucose, 4 mM glutamine, 10% heat-inactivated FCS, 1%100× non-essential amino acids, 10 mM HEPES, 100 U/ml penicillin andstreptomycin] are sown per well of a 384 multititer plate (from Greiner,TC plate, black with clear base) and incubated at 37° C./5% CO₂ for 24hours. Prior to the measurement, the medium is replaced by 30 μl ofcalcium dye loading buffer (FLIPR Calcium Assay, Molecular Devices) andincubated at 37° C./5% CO₂ for 60 minutes. The test substance isprepared in DMSO in various concentrations as a dose-response curve(starting concentration 10 mM, dilution factor 3.16) and prediluted 1:50with, for example, calcium-free Tyrode (130 mM NaCl, 5 mM KCl, 20 mMHEPES, 1 mM MgCl₂, 4.8 mM NaHCO₃, pH 7.4)/2 mM CaCl₂. For themeasurement of EP2 agonism, in a fluorescence measuring instrument(FLIPR Tetra®, Molecular Devices), 10 μl of the prediluted substancesolution are added to the calcium dye-laden cells, and the calcium fluxis determined by measuring the fluorescence at ex. 470 nm/em. 525 nm for120 seconds. Thereafter, the cells are incubated at 37° C./5% CO₂ for 10minutes. For the measurement of EP2 antagonism, the EP2 receptor isactivated in the FLIPR Tetra® by adding 20 μl of ˜22 nM (2×EC₅₀, finalconcentration) PGE2 in, for example, calcium-free Tyrode/2 mM CaCl₂, andthe calcium flux is determined by measuring the fluorescence at ex. 470nm/em. 525 nm for 120 seconds [lit.: C. R. Kennedy et al. (1999) Nat.Med. 5: 217-220; S. Narumiya and G. A. Fitzgerald (2001) J. Clin.Invest. 108: 25-30; N. Yang et al. (2003) J. Clin. Invest. 111:727-735].

B-14. In Vitro Test for EP3 Agonism and Antagonism

For the characterization of test substances in respect of EP3 agonismand antagonism, PGE2-induced calcium flux in EP3 (splice variant6)-expressing CHEM1 cells (Millipore, HTS092C) was used: 3000 cells in25 μl of plating medium [DMEM, 4.5 g/l glucose, 4 mM glutamine, 10%heat-inactivated FCS, 1% 100× non-essential amino acids, 10 mM HEPES,100 U/ml penicillin and streptomycin] are sown per well of a 384multititer plate (from Greiner, TC plate, black with clear base) andincubated at 37° C./5% CO₂ for 24 hours. Prior to the measurement, themedium is replaced by 30 μl of calcium dye loading buffer (FLIPR CalciumAssay, Molecular Devices) and incubated at 37° C./5% CO₂ for 60 minutes.The test substance is prepared in DMSO in various concentrations as adose-response curve (starting concentration 10 mM, dilution factor 3.16)and prediluted 1:50 with, for example, calcium-free Tyrode (130 mM NaCl,5 mM KCl, 20 mM HEPES, 1 mM MgCl₂, 4.8 mM NaHCO₃, pH 7.4)/2 mM CaCl₂.For the measurement of EP3 agonism, in a fluorescence measuringinstrument (FLIPR Tetra®, Molecular Devices), 10 μl of the predilutedsubstance solution are added to the calcium dye-laden cells, and thecalcium flux is determined by measuring the fluorescence at ex. 470nm/em. 525 nm for 120 seconds. Thereafter, the cells are incubated at37° C./5% CO₂ for 10 minutes. For the measurement of EP3 antagonism, theEP3 receptor is activated in the FLIPR Tetra® by adding 20 μl of ˜2 nM(2×EC₅₀, final concentration) PGE2 in, for example, calcium-freeTyrode/2 mM CaCl₂, and the calcium flux is determined by measuring thefluorescence at ex. 470 nm/em. 525 nm for 120 seconds [lit.: M. Kotaniet al. (1995) Mol. Pharmacol. 48: 869-879; M. Kotani et al. (1997)Genomics 40: 425-434; T. Kunikata et al. (2005) Nat. Immunol. 6:524-531; S. Narumiya and G. A. Fitzgerald (2001) J. Clin. Invest. 108:25-30; F. Ushikubi et al. (1998) Nature 395: 281-284].

B-15. In Vitro Test for EP4 Agonism and Antagonism

For the characterization of test substances in respect of EP4 agonismand antagonism, PGE2-induced calcium flux in EP4-expressing CHEM1 cells(Millipore, HTS142C) was used: 3000 cells in 25 μl of plating medium[DMEM, 4.5 g/l glucose, 4 mM glutamine, 10% heat-inactivated FCS, 1%100× non-essential amino acids, 10 mM HEPES, 100 U/ml penicillin andstreptomycin] are sown per well of a 384 multititer plate (from Greiner,TC plate, black with clear base) and incubated at 37° C./5% CO₂ for 24hours. Prior to the measurement, the medium is replaced by 30 μl ofcalcium dye loading buffer (FLIPR Calcium Assay, Molecular Devices) andincubated at 37° C./5% CO₂ for 60 minutes. The test substance isprepared in DMSO in various concentrations as a dose-response curve(starting concentration 10 mM, dilution factor 3.16) and prediluted 1:50with, for example, calcium-free Tyrode (130 mM NaCl, 5 mM KCl, 20 mMHEPES, 1 mM MgCl₂, 4.8 mM NaHCO₃, pH 7.4)/2 mM CaCl₂. For themeasurement of EP4 agonism, in a fluorescence measuring instrument(FLIPR Tetra®, Molecular Devices), 10 μl of the prediluted substancesolution are added to the calcium dye-laden cells, and the calcium fluxis determined by measuring the fluorescence at ex. 470 nm/em. 525 nm for120 seconds. Thereafter, the cells are incubated at 37° C./5% CO₂ for 10minutes. For the measurement of EP4 antagonism, the EP4 receptor isactivated in the FLIPR Tetra® by adding 20 μl of ˜26 nM (2×EC₅₀, finalconcentration) PGE2 in, for example, calcium-free Tyrode/2 mM CaCl₂, andthe calcium flux is determined by measuring the fluorescence at ex. 470nm/em. 525 nm for 120 seconds [lit.: S. Narumiya and G. A. Fitzgerald(2001) J. Clin. Invest. 108: 25-30; M. Nguyen et al. (1997) Nature 390:78-81; K. Yoshida et al. (2002) Proc. Natl. Acad. Sci. USA 99:4580-4585].

B-16. In Vitro Test for IP Agonism and Antagonism

For the characterization of test substances in respect of IP agonism andantagonism, iloprost-induced calcium flux in IP-expressing CHEM1 cells(Millipore, HTS131C) was used: 3000 cells in 25 μl of plating medium[DMEM, 4.5 g/l glucose, 4 mM glutamine, 10% heat-inactivated FCS, 1%100× non-essential amino acids, 10 mM HEPES, 100 U/ml penicillin andstreptomycin] are sown per well of a 384 multititer plate (from Greiner,TC plate, black with clear base) and incubated at 37° C./5% CO₂ for 24hours. Prior to the measurement, the medium is replaced by 30 μl ofcalcium dye loading buffer (FLIPR Calcium Assay, Molecular Devices) andincubated at 37° C./5% CO₂ for 60 minutes. The test substance isprepared in DMSO in various concentrations as a dose-response curve(starting concentration 10 mM, dilution factor 3.16) and prediluted 1:50with, for example, calcium-free Tyrode (130 mM NaCl, 5 mM KCl, 20 mMHEPES, 1 mM MgCl₂, 4.8 mM NaHCO₃, pH 7.4)/2 mM CaCl₂. For themeasurement of IP agonism, in a fluorescence measuring instrument (FLIPRTetra®, Molecular Devices), 10 μl of the prediluted substance solutionare added to the calcium dye-laden cells, and the calcium flux isdetermined by measuring the fluorescence at ex. 470 nm/em. 525 nm for120 seconds. Thereafter, the cells are incubated at 37° C./5% CO₂ for 10minutes. For the measurement of IP antagonism, the IP receptor isactivated in the FLIPR Tetra® by adding 20 μl of ˜106 nM (2×EC₅₀, finalconcentration) iloprost in, for example, calcium-free Tyrode/2 mM CaCl₂,and the calcium flux is determined by measuring the fluorescence at ex.470 nm/em. 525 nm for 120 seconds [lit.: S. Narumiya et al. (1999)Physiol. Rev. 79: 1193-1226; T. Murata et al. (1997) Nature 388:678-682; Y. Cheng et al. (2002) Science 296: 539-541; C. H. Xiao et al.(2001) Circulation 104: 2210-2215; G. A. Fitzgerald (2004) N. Engl. J.Med. 351: 1709-1711].

B-17. In Vitro Test for TP Agonism and Antagonism

For the characterization of test substances in respect of TP agonism andantagonism, U46619-induced calcium flux in TP-expressing CHEM1 cells(Millipore, HTS081C) was used: 3000 cells in 25 μl of plating medium[DMEM, 10% heat-inactivated FCS, 10% heat-inactivated FCS, 1% 100×non-essential amino acids, 10 mM HEPES, 0.25 mg/ml Geneticin (G418), 100U/ml penicillin and streptomycin] are sown per well of a 384 multititerplate (from Greiner, TC plate, black with clear base) and incubated at37° C./5% CO₂ for 24 hours. Prior to the measurement, the medium isreplaced by 30 μl of calcium dye loading buffer (FLIPR Calcium Assay,Molecular Devices) and incubated at 37° C./5% CO₂ for 60 minutes. Thetest substance is prepared in DMSO in various concentrations as adose-response curve (starting concentration 10 mM, dilution factor 3.16)and prediluted 1:50 with, for example, calcium-free Tyrode (130 mM NaCl,5 mM KCl, 20 mM HEPES, 1 mM MgCl₂, 4.8 mM NaHCO₃, pH 7.4)/2 mM CaCl₂.For the measurement of TP agonism, in a fluorescence measuringinstrument (FLIPR Tetra®, Molecular Devices), 10 μl of the predilutedsubstance solution are added to the calcium dye-laden cells, and thecalcium flux is determined by measuring the fluorescence at ex. 470nm/em. 525 nm for 120 seconds. Thereafter, the cells are incubated at37° C./5% CO₂ for 10 minutes. For the measurement of TP antagonism, theTP receptor is activated in the FLIPR Tetra® by adding 20 μl of ˜88 nM(2×EC₅₀, final concentration) U46619 in, for example, calcium-freeTyrode/2 mM CaCl₂, and the calcium flux is determined by measuring thefluorescence at ex. 470 nm/em. 525 nm for 120 seconds [lit.: S. Ali etal. (1993) J. Biol. Chem. 268: 17397-17403; K. Hanasaki et al. (1989)Biochem. Pharmacol. 38: 2967-2976; M. Hirata et al. (1991) Nature 349:617-620].

B-18. Animal Model of Bleomycin-Induced Pulmonary Fibrosis

Bleomycin-induced pulmonary fibrosis in the mouse or rat is a widelyused animal model of pulmonary fibrosis. Bleomycin is a glycopeptideantibiotic employed in oncology for the therapy of testicular tumors andHodgkin- and Non-Hodgkin tumors. It is eliminated renally, has ahalf-life of about 3 hours and, as cytostatic, influences various phasesof the division cycle [Lazo et al., Cancer Chemother. 15, 44-50 (1994)].Its anti-neoplastic effect is based on an oxidatively damaging effect onDNA [Hay et al., Arch. 65, 81-94 (1991)]. Lung tissue is at a particularrisk when exposed to bleomycin since it contains only a small number ofcysteine hydrolases which, in other tissues, lead to inactivation ofbleomycin. Following administration of bleomycin, the animals suffer anacute respiratory distress syndrome (ARDS) with subsequent developmentof pulmonary fibrosis.

Administration of bleomycin may be by single or repeat intratracheal,inhalative, intravenous or intraperitoneal administration. Treatment ofthe animals with the test substance (by gavage, by addition to the feedor drinking water, using an osmotic minipump, by subcutaneous orintraperitoneal injection or by inhalation) starts at the day of thefirst bleomycin administration or therapeutically 3-14 days later andextends over a period of 2-6 weeks. At the end of the study, abronchio-alveolar lavage to determine the cell content and thepro-inflammatory and pro-fibrotic markers and a histological assessmentof pulmonary fibrosis are carried out.

B-19. Animal Model of DQ12 Quartz-Induced Pulmonary Fibrosis

DQ12 quartz-induced pulmonary fibrosis in the mouse or rat is a widelyused animal model of pulmonary fibrosis [Shimbori et al., Exp. Lung Res.36, 292-301 (2010)]. DQ12 quartz is quartz which is highly active owingto breaking or grinding. In mice and rats, intratracheal or inhalativeadministration of DQ12 quartz leads to alveolar proteinosis followed byinterstitial pulmonary fibrosis. The animals receive a single or repeatintratracheal or inhalative instillation of DQ12 quartz. Treatment ofthe animals with the test substance (by gavage, by addition to the feedor drinking water, using an osmotic minipump, by subcutaneous orintraperitoneal injection or by inhalation) starts at the day of thefirst silicate instillation or therapeutically 3-14 days later andextends over a period of 3-12 weeks. At the end of the study, abronchio-alveolar lavage to determine the cell content and thepro-inflammatory and pro-fibrotic markers and a histological assessmentof pulmonary fibrosis are carried out.

B-20. Animal Model of DQ12 Quartz or FITC-Induced Pulmonary Inflammation

In the mouse and the rat, intratracheal administration of DQ12 quartz orfluorescein isothiocyanate (FITC) leads to an inflammation in the lung[Shimbori et al., Exp. Lung Res. 36, 292-301 (2010)]. At the day of theinstillation of DQ12 quartz or FITC or a day later the animals aretreated with the test substance for a duration of 24 h up to 7 days (bygavage, by addition to the feed or drinking water, using an osmoticminipump, by subcutaneous or intraperitoneal injection or byinhalation). At the end of the experiment, a bronchio-alveolar lavage todetermine the cell content and the pro-inflammatory and pro-fibroticmarkers is carried out.

C. WORKING EXAMPLES OF PHARMACEUTICAL COMPOSITIONS

The compounds of the invention can be converted to pharmaceuticalpreparations as follows:

Tablet: Composition:

100 mg of the compound of the invention, 50 mg of lactose (monohydrate),50 mg of corn starch (native), 10 mg of polyvinylpyrrolidone (PVP 25)(BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.

Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.

Production:

The mixture of compound of the invention, lactose and starch isgranulated with a 5% solution (w/w) of the PVP in water. The granulesare dried and then mixed with the magnesium stearate for 5 minutes. Thismixture is compressed using a conventional tableting press (see abovefor format of the tablet). The guide value used for the pressing is apressing force of 15 kN.

Suspension for Oral Administration: Composition:

1000 mg of the compound of the invention, 1000 mg of ethanol (96%), 400mg of Rhodigel® (xanthan gum from FMC, Pennsylvania, USA) and 99 g ofwater.

10 ml of oral suspension correspond to a single dose of 100 mg of thecompound of the invention.

Production:

The Rhodigel is suspended in ethanol; the compound of the invention isadded to the suspension. The water is added while stirring. The mixtureis stirred for about 6 h until the swelling of the Rhodigel is complete.

Solution for Oral Administration: Composition:

500 mg of the compound of the invention, 2.5 g of polysorbate and 97 gof polyethylene glycol 400. 20 g of oral solution correspond to a singledose of 100 mg of the compound of the invention.

Production:

The compound of the invention is suspended in the mixture ofpolyethylene glycol and polysorbate with stirring. The stirringoperation is continued until dissolution of the compound of theinvention is complete.

i.v. solution:

The compound of the invention is dissolved in a concentration below thesaturation solubility in a physiologically acceptable solvent (e.g.isotonic saline solution, glucose solution 5% and/or PEG 400 solution30%). The solution is subjected to sterile filtration and dispensed intosterile and pyrogen-free injection vessels.

1-11. (canceled)
 12. A method for treatment and/or prevention of adisease or a disorder in a human or an animal comprising administeringto the human or animal in need thereof a compound of the formula (I)

in which R^(A) is hydrogen, halogen, pentafluorosulfanyl, cyano, nitro,(C₁-C₄)-alkyl, hydroxyl, (C₁-C₄)-alkoxy, amino or a group of the formula—NH—C(═O)—R⁶, —NH—C(═O)—NH—R⁶ or —S(═O)_(n)—R⁷, where (C₁-C₄)-alkyl and(C₁-C₄)-alkoxy may be up to trisubstituted by fluorine, and in which R⁶is hydrogen or (C₁-C₄)-alkoxy which may be up to trisubstituted byfluorine, R⁷ is (C₁-C₄)-alkyl which may be substituted by hydroxyl,methoxy or ethoxy or up to trisubstituted by fluorine, and n is thenumber 0, 1 or 2, D is C—R^(D) or N, E is C—R^(E) or N, G is C—R^(G) orN, where not more than two of the ring members D, E and G at the sametime are N, and in which R^(D) and R^(E) are each independentlyhydrogen, fluorine, chlorine, methyl, trifluoromethyl, methoxy ortrifluoromethoxy, and R^(G) is hydrogen, fluorine, chlorine, bromine,methyl or trifluoromethyl, Z is OH or a group of the formula —NH—R⁸,—NH—SO₂—R⁹ or —NH—SO₂—NR^(10A)R^(10B), in which R⁸ is hydrogen or(C₁-C₄)-alkoxy which may be up to trisubstituted by fluorine, R⁹ is(C₁-C₄)-alkoxy which may be up to trisubstituted by fluorine, or phenyl,and R^(10A) and R^(10B) are each independently hydrogen or (C₁-C₄)-alkylwhich may be up to trisubstituted by fluorine, R¹ is halogen,trifluoromethoxy, (trifluoromethyl)sulfanyl, pentafluorosulfanyl,(C₁-C₄)-alkyl, trimethylsilyl, cyclopropyl or cyclobutyl, where(C₁-C₄)-alkyl may be up to trisubstituted by fluorine and cyclopropyland cyclobutyl may be up to disubstituted by fluorine, R², R³ and R⁴ areeach independently hydrogen, fluorine, chlorine, methyl ortrifluoromethyl, R⁵ is (C₁-C₄)-alkyl which may be up to trisubstitutedby fluorine, or is fluorine, chlorine, methoxy or cyclopropyl, and Ar isphenyl which may be mono- or disubstituted identically or differently byfluorine and chlorine, or is pyridyl or thienyl, and the N-oxides,salts, solvates, salts of the N-oxides and solvates of the N-oxides andsalts thereof.
 13. The method of claim 12, wherein the disease ordisorder is selected from the group consisting of: idiopathic pulmonaryfibrosis, pulmonary hypertension, bronchiolitis obliterans syndrome,inflammatory skin, fibrotic skin, eye disorder, and fibrotic disorder ofan internal organ.
 14. The method of claim 12, wherein the compound ofthe formula (I) is in a medicament, wherein the medicament comprises thecompound of the formula (I) in combination with one or more inert,nontoxic, pharmaceutically suitable excipients.
 15. The method of claim14 wherein the medicament further comprises at least one selected fromthe group consisting of PDE 5 inhibitor, sGC activator, sGC stimulator,prostacyclin analog, IP receptor agonist, endothelin antagonist,compound that inhibit the signal transduction cascade, and pirfenidone.16. The method of claim 12, wherein the compound is a compound offormula (I) in which R^(A) is hydrogen, fluorine, chlorine, bromine,cyano, methyl, trifluoromethyl, methoxy, trifluoromethoxy or a group ofthe formula —S(═O)_(n)—R⁷ in which R⁷ is methyl or trifluoromethyl, andn is the number 0 or 2, D is C—R^(D) or N, in which R^(D) is hydrogen orfluorine, E is C—H, G is C—R^(G) or N, in which R^(G) is hydrogen,fluorine or chlorine, Z is OH, R¹ is chlorine, bromine, iodine, methyl,ethyl, isopropyl, trifluoromethyl, trifluoromethoxy,(trifluoromethyl)sulfanyl, pentafluorosulfanyl or trimethylsilyl, R² andR³ are each hydrogen, R⁴ is hydrogen, fluorine or chlorine, R⁵ ismethyl, chlorine or cyclopropyl, and Ar is phenyl which may bemonosubstituted by fluorine, or pyridyl, and the salts, solvates andsolvates of the salts thereof.
 17. The method of claim 12, wherein thecompound is a compound of formula (I) in which R^(A) is fluorine,chlorine, cyano, methyl, trifluoromethyl, methoxy, trifluoromethoxy or agroup of the formula —S(═O)_(n)—R⁷ in which R⁷ is methyl ortrifluoromethyl, and n is the number 0 or 2, D is C—H, E is C—H, G isC—R^(G) or N, in which R^(G) is hydrogen, fluorine or chlorine, Z is OH,R¹ is chlorine, bromine, methyl, trifluoromethyl or trimethylsilyl, R²and R³ are each hydrogen, R⁴ is hydrogen or chlorine, R⁵ is methyl, andAr is phenyl which may be monosubstituted by fluorine, or 4-pyridyl, andthe salts, solvates and solvates of the salts thereof.